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DOI: 10.1002/asia.201100432
Click Chemistry: 1,2,3-Triazoles as Pharmacophores
Sandip G. Agalave, Suleman R. Maujan, and Vandana S. Pore*[a]
On the occasion of the 10th anniversary of click chemistry
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Abstract: The copper(I)-catalyzed 1,2,3-triazole-forming
reaction between azides and terminal alkynes has become
the gold standard of click chemistry due to its reliability,
specificity, and biocompatibility. Applications of click
chemistry are increasingly found in all aspects of drug discovery; they range from lead finding through combinatorial chemistry and target-templated in vitro chemistry, to
proteomics and DNA research by using bioconjugation
reactions. The triazole products are more than just passive
1. Introduction
Examination of the molecules created by nature reveals an
overall preference for carbon–heteroatom bonds over
carbon–carbon bonds; for example, nucleic acids, proteins,
and polysaccharides are condensation polymers of subunits
linked through carbon–heteroatom bonds. This strategy of
making large oligomers from relatively simple building
blocks can be described as natures way of performing combinatorial chemistry with remarkable modularity and diversity.
Since Sharpless and co-workers seminal report[1] on the
so called click chemistry concept, a huge number of papers
have been published[2] on the copper(I)-catalyzed azidealkyne cycloaddition (CuAAC) to give under mild conditions 1,4-disubstituted 1,2,3-triazoles in very high yields,
with dramatic rate acceleration. This metal-catalyzed reaction discovered independently in the Sharpless and Meldal
laboratories[3] constitutes a substantial improvement of the
classical Huisgen-type thermal 1,3-dipolar cycloaddition,[4, 5]
which affords mixtures of 1,4- and 1,5-disubstituted triazoles.
It has been amply documented that this highly regioselective
triazole annulation served as a powerful ligation tool of the
most disparate molecular fragments, thus leading to the
metaphoric view of the triazole ring as a robust keystone in
complex molecular architectures.[6] Since the pioneering investigations at Scripps, this commendably straightforward
chemistry (which can be conducted in aqueous media) has
been widely applied as a powerful tool for the selective
modifications of enzymes,[7] viruses,[8]and cells.[9]
Click chemistry is a modular synthetic approach towards
the assembly of new molecular entities. The wide scope of
CuAAC is firmly demonstrated by its use in different areas
of life and material sciences such as drug discovery,[10] bioconjugation,[11] polymer and materials science,[12] and related
areas[13] including supramolecular chemistry.[14] DNA labeling[15] and oligonucleotide synthesis,[16] assembly of glyco-
[a] S. G. Agalave, Dr. S. R. Maujan, Dr. V. S. Pore
Organic Chemistry Division
National Chemical Laboratory
Dr. Homi Bhabha Road, Pashan, Pune (India)
Fax: (+ 91) 20-25902629
E-mail: [email protected]
Chem. Asian J. 2011, 6, 2696 – 2718
linkers; they readily associate with biological targets,
through hydrogen-bonding and dipole interactions. The
present review will focus mainly on the recent literature
for applications of this reaction in the field of medicinal
chemistry, in particular on use of the 1,2,3-triazole moiety
as pharmacophore.
Keywords: click chemistry · copper · cycloaddition · pharmacophores · triazoles
clusters[17] and glycodendrimers,[18] preparation of stationary
phases for HPLC column,[19] development of microcontact
printing,[20] conjugation of molecular cargos to the headgroup of phospholipids,[21] and construction of bolaamphiphilic structures[22] are further examples of the use of
CuAAC.
The present review will focus mainly on the recent literature (up to February 2011) for applications of this reaction
in the field of medicinal chemistry, in particular on use of
1,2,3-triazole moiety as pharmacophore. Since this is an extremely fast developing area, this review offers important
knowledge to the interested readers.
2. Reviews on Click Chemistry
The concept of click chemistry is experiencing growing popularity. A large amount of literature—including excellent
review articles—is available on this subject. In 2003, Kolb
and Sharpless et al.[23] presented a review that outlined the
special nature of triazole chemistry with an emphasis on the
potential use of the reaction in biochemical studies that
range from lead discovery and optimization to tagging of
biological systems, such as proteins, nucleotides, and whole
organisms. Bock et al. presented a review with an in-depth
analysis of the reaction in 2006, including all essential mechanistic and methodological aspects at the time.[24] Binder
et al.[25] and Lutz[26] described the polymer and materials science applications. Gil et al.,[27] Li et al.,[28] Moses and Moorhouse,[29] and Wu and Fokin[30] have reviewed the general
synthetic utility of click chemistry across the fields.
Other reviews mention CuAAC as essential in particular
important fields, for example, in dendrimer and polymer
grafting,[31–33] as well as in synthesis[34, 35] and in chemical ligation.[36, 37] Reviews also describe applications in synthesis of
peptidomimetics,[38, 39] in bioconjugations[40–42] and surface
chemistry.[43] It has been compared to the Staudinger ligation[37] and used in profiling of proteases[44] and in combinatorial drug discovery.[45, 46] A review on a metal-chelating
system has also been published.[47] An excellent recent
review by Meldal and Tornoe describes CuAAC in great
detail.[48] The design of the recent development of fluorogenic CuAAC reactions as well as their applications has
been highlighted by Wang et al.[49]
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The basic heterocyclic rings present in the various medicinal agents are mainly 1,2,3-triazole and 1,2,4-triazole. A
large volume of research has been carried out on triazole
and their derivatives, which has proven the pharmacological
importance of this heterocyclic nucleus. Kharb et al. have reviewed[50] the pharmacological activities of triazole derivatives with an update of recent research findings. A focused
review on the most significant achievements in the discovery
of antifungal lead structures within last few years is presented by Sheng and Zhang.[51] In particular, the structure–activity relationship of antifungal leads and perspectives for
future antifungal drug discovery is provided.
3. Biologically Active 1,2,3-Triazoles
There are very few 1,2,3-triazole-containing molecules on
the market or are in the last stage of clinical trials. Potential
pharmaceuticals based on 1,2,3-triazoles include the anticancer compound carboxyamidotriazole (CAI),[52] the nucleoside derivative non-nucloside reverse transcriptase inhibitor
tert-butyldimethylsilylspiroaminooxathioledioxide
(known as TSAO),[53] b-lactum antibiotic Tazobactum, the
cephalosporine Cefatrizine, and so on (Scheme 1).
Sandip G. Agalave was born in 1987 in
Pune of Maharashtra State, India. He received his Bachelor’s degree in 2007 from
the University of Pune. He completed his
Master’s degree in Organic Chemistry in
2009 at the University of Pune. After finishing his Master’s degree, he joined as a
research student under the supervision of
Dr. Mrs. V. S. Pore in the National Chemical Laboratory, Pune, India. His research
focuses mainly on design and synthesis of
new drug molecules.
Scheme 1. Potential pharmaceuticals based on 1,2,3-triazoles.
Suleman R. Maujan was born in 1981 in
Shirur Anantpal of Maharashtra State,
India. He got his Bachelor’s degree in
2001 and further he continued his studies
in Organic Chemistry to get Master’s
degree in 2003 from Swami Ramanand
Teerth Marathwada University, Nanded,
India. He got his Ph. D. degree under the
supervision of Dr. H. B. Borate at the National Chemical Laboratory, Pune in
2010. His PhD work was mainly focused
on the synthetic studies of fluconazole analogues. His research interests include the
design and synthesis of important intermediates and (un)natural products of biological interest.
Vandana Pore was born in 1956 in Pune
of Maharashtra State, India. She received
her M. Sc. degree in Organic Chemistry
in 1978 from the University of Pune. She
then completed her doctoral research at
the National Chemical Laboratory under
the supervision of Dr. Braja Gopal Hazra
in the area of synthesis of steroidal plant
hormones-brassinosteroids. The University of Pune awarded her a Ph. D. in 1991.
She continued her research career at the
NCL as a research scientist working particularly in developing multistep synthetic
routes to steroidal molecules such as brassinosteroids, mifepristone, squalamine, and so on. She is the author of
more than 45 papers and three US patents. Her research interests are the
design and synthesis of bile acid-based drug molecules.
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3.1. Biologically Active 1,2,3-Triazoles Synthesized without
Copper Catalysis
Although demand for new chemical materials and biologically active molecules continues to grow, chemists have
hardly begun to explore the vast pool of potentially active
compounds.[54] In the scenario of a continuous request for
better drugs in shorter times, it is a challenging task for medicinal chemists to prepare new patentable molecules that
combine high activity and selectivity, drug-likeness, and
good pharmacokinetic properties.
There are large number of molecules that contain 1,2,3triazole moiety with a variety of biological activities and
that were synthesized before the approach of click chemistry was developed. A few examples are shown in Scheme 2.
Various methods have been used for their synthesis except
copper-catalyzed click reaction.
4. Click Reactions and the Pharmacological
Applications of 1,2,3-Triazoles
The emerging field of click chemistry offers a unique approach to the synthesis of 1,2,3-triazole-containing molecules. This reaction owes its usefulness in part to the ease
with which azides and alkynes can be introduced into a molecule and their relative stability under a variety of condi-
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1,2,3-Triazoles as Pharmacophores
than the corresponding basic nitrogen atoms of iminosugars.[57]
In their review article Meldal
and Tornoe summarized triazolecontaining enzyme inhibitors and
receptor ligands.[48] They also collected 1,2,3-trizole-modified natural products. Angell and Burgess
gathered 1,2,3-triazole-containing
peptides.[39] In this review, we have
collected the 1,2,3-triazole molecules according to their biological
activities.
4.1. Anticancer
Cancer is a major public health
burden in both developed and developing countries. Several anticancer agents including taxol, vinblastine, vincristine, camptothecin
derivatives, topotecan and irinotecan, and etoposide derived from
epipodophyllotoxin are in clinical
use all over the world. A number
of promising agents such as flavopiridol, roscovitine, combretastatin
Scheme 2. 1,2,3-Triazole-containing molecules with different biological activities.
A-4, betulinic acid, and silvestrol
are in clinical or preclinical development. However, there is a need to screen new molecules
tions. Azides and alkynes are essentially inert to most biowith different modes of actions, compounds active for other
logical and organic conditions, molecular oxygen, water, and
diseases that might show anticancer activity, and also new
the majority of common reaction conditions in organic synanalogues of available clinical agents.
thesis.[55]
M. J. Fray et al. reported a series of 6,7-dichloro-1,4-dihy1,2,3-Triazole moieties are attractive connecting units bedro-(1 H,4 H)-quinoxaline-2,3-diones (Scheme 3, 1) in which
cause they are stable to metabolic degradation and capable
of hydrogen bonding, which can
be favorable in the binding of
biomolecular targets and can
improve the solubility.[56] The
1,2,3-triazole moiety does not
occur in nature, although the
synthetic molecules that contain
1,2,3-triazole units show diverse
biological activities. The importance of triazolic compounds in
medicinal chemistry is undeniable. Contrary to other azaheterocycles, the 1,2,3-triazole
ring is not protonated at physiological pH because of its poor
basicity. Hence, the nonprotonated sp2-hybridized nitrogen
atoms of 1,2,3-triazoles may
better mimic the partial positive
charge at the anomeric carbon
in the transition state of the
glucosidase-catalyzed reaction Scheme 3. Structures 1–4 and the synthesis of the 1,2,3-triazoles.
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the 5-position substituent was a heterocyclylmethyl or 1(heterocyclyl)-1-propyl group.[58] Most of the compounds
contain a 1,2,3-triazole ring as a heterocyclic ring. The most
potent compound in the series was 6,7-dichloro-5-[1-(1,2,4triazol-4-yl)propyl]-1,4-dihydro-(1 H,4 H)-quinoxaline-2,3dione. Its brain penetration extent was also reported.
Synthesis of 4-aryl-1,2,3-triazoles (Scheme 3, 2) as inhibitors of human methionine aminopeptidase type 2
(hMetAP2) has been reported by Kallander et al. as anticancer agents.[59] Synthesis of these compounds was achieved
in two steps as shown in Scheme 3. N1 and N2 nitrogen
atoms of the triazole moiety actively participate in binding
to the active site of enzyme and are the key elements for inhibition.
Pagliai et al. reported the synthesis of a large number of
triazole derivatives of resveratrol (Scheme 3, 3) by means of
a parallel combinatorial approach that used a typical click
reaction.[60] Some of these compounds exhibited antiproliferative activity.
a-GalCer is the most potent agonistic antigen of a natural
killer T-cell receptor. Lee et al. prepared a series of 1,2,3-triazole-containing a-GalCer analogues (Scheme 3, 4) in which
the lipid chain lengths were incrementally varied.[61] Isosteric
replacement of the amide moiety of a-GalCer with a triazole increased the IL-4 versus IFN-g bias of released cytokines. The stimulatory effect was influenced by the length of
the attached chain; the long-chained 1,2,3-triazole analogues
showed comparable stimulatory effect on cytokine production as a-GalCer and exhibit a stronger Th2 cytokine response.
A small library of isatins modified with fluorinated aromatic groups and heterocycles was synthesized by Smith and
co-workers.[62] A lead compound that incorporated 2’-fluoroethyl-1,2,3-triazole was identified with subnanomolar affinity for caspase 3. The compound showed high stability in
vitro with rapid uptake and elimination in healthy tissues
and tumors. 18F-labeled isatin has been proposed to be a
candidate radiotracer for preclinical evaluation of apoptosis
imaging.
Yim et al. described the synthesis and biological evaluation of a series of 1,4,7,10-tetraazacyclododecane-1,4,7,10tetraacetic acid (DOTA)-conjugated monomeric, dimeric,
and tetrameric [Tyr3]octreotide-based analogues as a tool
for tumor imaging and/or radionuclide therapy.[63] These
compounds were synthesized using CuI-catalyzed 1,3-dipolar
cycloaddition between peptidic azides and dendrimer-derived alkynes and subsequent metal-free introduction of
DOTA by means of thio-acid/sulfonyl azide amidation
(“sulfo-click” reaction). In a competitive binding assay using
rat pancreatic AR42J tumor cells, the monomeric [Tyr3]octreotide conjugate displayed the highest binding affinity
(IC50 = 1.32 nm) followed by dimeric [Tyr3]octreotide
(2.45 nm), and tetrameric [Tyr3]octreotide (14.0 nm).
The epidermal growth factor receptor (EGFR/c-ErbB1/
HER1) is overexpressed in many cancers including breast,
ovarian, endometrial, and non-small-cell lung cancer. An epidermal growth factor receptor (EGFR)-specific imaging
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agent could facilitate the clinical evaluation of primary
tumors and/or metastases. To achieve this goal, Pisaneschi
et al. synthesized a small array of fluorine-containing compounds based on a 3-cyanoquinoline core.[64] On the basis of
its high affinity for EGFR kinase (IC50 = (1.81 0.18) nm),
good cellular potency (IC50 = (21.97 9.06) nm), low lipophilicity, and good metabolic stability, compound 5, which in-
corporated 20-fluoroethyl-1,2,3-triazole, was selected for
evaluation as a radioACHTUNGREliACHTUNGREgand. This compound showed good
stability in vitro and a fourfold-higher uptake in highEGFR-expressing A431 tumor xenografts relative to lowEGFR-expressing HCT116 tumor xenografts.
Imperio et al. reported synthesis of steganacin and podophyllotoxin analogues that present a triazole moiety in place
of the lactone ring (compound 6).[65] The synthesized compounds were found to be cytotoxic with retention of antitubulin activity.
A library of sugar 1,2,3-triazoles was synthesized by Carvalho et al. by using click chemistry from galactose derivatives that contained either a C6 or C1 azide group (compound 7).[66] These compounds proved to be moderate Trypanosoma cruzi trans-sialidase (TcTS) inhibitors in vitro (<
40 % inhibition at 1 mm concentration), and acceptor substrates for TcTS-catalyzed trans-sialylation. Some of the
sugar triazoles showed trypanocidal activity in the low-hundreds of micromolar range against cultured trypomastigote
forms of T. cruzi. Assessment of these compounds against
cultured mouse spleen cells suggested specific mode of antiparasite action rather than a generic cytotoxic effect.
Several bisdaunorubicins were effectively constructed by
Zhang et al. by click reaction using (EtO)3PCuI as catalyst
in organic solvent.[67] Bisdaunorubicins with various lengths
and flexibility of the linkers between two monomers were
synthesized. The cytotoxicity studies indicated that the compound with shorter linker displays higher activity against
cancer cells, whereas the flexibility of the linker also contributes to their activity.
Combretastatin A-4 is an antitumoral and antitubulin
agent that is active only in its cis configuration. Cafici et al.
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1,2,3-Triazoles as Pharmacophores
synthesized cis-locked combretastatins that contained a triazole ring (combretatriazoles).[68] They developed column
chromatography-free parallel solution-phase synthesis of
1,5-disubstituted triazoles. Their antitubulinic activity identified three new compounds with high potency and new mechanism of action that induces cells to appear multinucleated
and display a high number of mitotic spindles.
A series of cis-restricted 1,5-disubstituted 1,2,3-triazole
analogues of combretastatin A-4 were also prepared by
Odlo et al.[69] One of the triazoles, 2-methoxy-5-[1-(3,4,5-trimethoxyphenyl)-1 H-1,2,3-triazol-5-yl]aniline (8) displayed
potent cytotoxic activity against several cancer cell lines
with IC50 values in the nanomolar range. Molecular modeling experiments that involved these molecules and the colchicines binding site of a,b-tubulin showed that the triazole
moiety interacts with b-tubulin by means of hydrogen bonding with several amino acids.
Yoon and co-workers developed a synthetic protocol for
rapid assembly of 28-membered lavendustin-mimetic small
molecules by using click chemistry.[70] These molecules were
evaluated against cancer cell lines. One of the molecules in
which X = PhACHTUNGRE(CH2)3 (9) showed cytotoxic activity on the
CCRF-CEM leukemia cell line with GI50 value of 0.9 mm.
A series of triazole-containing novobiocin analogues (10)
were designed, synthesized, and their biological activity was
determined by Peterson and co-workers.[71] These compounds contain a triazole ring in lieu of the amide moiety
present in the natural product. The anti-proliferative effects
of these compounds were evaluated against two breastcancer-cell lines (SKBr-3 and MCF-7). The triazole moiety
has little effect on the anti-proliferative activity. Both the
triazole and amide analogues that contain biaryl and 3indole side chains indicated comparable activities for both
sets of compounds against the two cell lines tested. One discrepancy was observed between the amide and triazole analogues that contained simple aryl side chains. The amidecontaining molecules manifested IC50 values in the 10–20 mm
Chem. Asian J. 2011, 6, 2696 – 2718
range, whereas the triazole compounds displayed IC50 values
above 50 mm. These results suggested that the triazole
moiety affects biological activity in two ways: the availability of a hydrogen-bond donor in the amide linkage and the
steric bulk of the side chain.
Novel
20,30-dideoxy-20,30-diethanethioribonucleosides
and those modified with a triazole ring were prepared in excellent yields and their antitumor activity was evaluated by
Yu et al.[72] The series of triazole-modified nucleosides (11)
showed significantly improved antitumor activity towards
HepG2, A549, and Hela cell lines and higher cytotoxicity towards HepG2, LAC, and Hela
cell lines relative to the control
drug floxuridine. These results
suggested that the conjugation
effect of triazole ring with aromatic system is important for
bioactivity.
A series of two classes of 3phenylpyrazolopyrimidine–
1,2,3-triazole conjugates (12)
were synthesized by Kumar and
his group by using a click
chemistry approach.[73] All the
compounds were evaluated for
inhibition of Src kinase and
human ovarian adenocarcinoma
(SK-Ov-3), breast carcinoma
(MDA-MB-361), and colon adenocarcinoma (HT-29). Hexyltriazolyl-substituted 3-phenylpyrazolopyrimidine exhibited inhibition of Src kinase with
an IC50 value of 5.6 mm. 4-Methoxyphenyl triazolyl-substituted 3-phenylpyrazolopyrimidine inhibited the cell proliferation of HT-29 and SK-Ov-3 by 73 % and 58 %, respectively,
at a concentration of 50 mm.
Two classes of 1,4-disubstituted 1,2,3-triazoles (13) were
synthesized by Kumar et al. by using a one-pot reaction of
a-tosyloxy ketones/a-halo ketones, sodium azide, and terminal alkynes in the presence of aqueous PEG by using a click
chemistry approach;[74] they were evaluated for Src kinase
inhibitory activity. Structure–activity relationship analysis
demonstrated that insertion of C6H5- and 4-CH3C6H4- at the
4-position for both classes and a less bulky aromatic group
at the 1-position in class 1 contributed critically to the
modest Src inhibition activity (IC50 = 32–43 mm) of 1,4-disubstituted 1,2,3-triazoles.
Yan and co-workers prepared a series of heterocyclefused 1,2,3-triazoles by the 1,3-dipolar cycloaddition of heterocyclic ketene aminals or N,O-acetals with sodium azide
and polyhalo isophthalonitriles in a one-pot reaction at
room temperature without catalyst; they were evaluated in
vitro against a panel of human tumor cell lines.[75] 1,3-Oxazoheterocycle fused 1,2,3-triazoles (14) were more potent
against the tumor cell lines Skov-3, HL-60, A431, A549, and
HepG-2 than 1,3-diazoheterocycle fused 1,2,3-triazoles. 4Methoxyphenyl-substituted
1,3-oxazoheterocycle-fused
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1,2,3-triazole 15 was found to be the most potent derivative
with IC50 values lower than 1.9 mg mL 1 against A431 and
K562 human tumor cell lines.
The mesenchymal-epithelial transition factor (c-Met),
which is related to tumor cell growth, angiogenesis, and
metastases, is known to be overexpressed in several tumor
types. Kim et al. synthesized technetium-99m-labeled 1,2,3triazole-4-yl c-Met binding peptide (cMBP) derivatives
(16 a–c), by solid-phase peptide synthesis and the click-tochelate protocol for the introduction of tricarbonyl technetium-99m, as a potential c-Met receptor kinase positive
tumor imaging agent, and evaluated their in vitro c-Met
binding affinity, cellular uptake, and stability.[76] The 99mTclabeled cMBP derivatives were prepared in 85–90 % radiochemical yields. The cold surrogate Re-labeled cMBP derivatives were found to have high binding affinities (0.06–
0.16 mm) relative to purified cMet/Fc chimeric recombinant
protein. In vitro cellular uptake and inhibition studies demonstrated the high specific binding of 99mTc-labeled cMBP
derivatives to c-Met receptor positive U87MG cells.
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Structurally diverse conjugates that contained a central
di-1,2,3-triazole with novel tridentate metal-chelating systems were synthesized by Mindt et al.[77] These conjugates
were found to be efficient ligand systems for the chelation
of fac-[M(CO)3ACHTUNGRE(H2O)3](+) (M = 99mTc, Re) and yielded welldefined and stable complexes. The organometallic 99mTc conjugates were found to be suitable for application as diagnostic radiotracers for single-photon emission computed tomography (SPECT) as demonstrated in vitro with a fragment of
tumor-targeting bombesin peptide functionalized with a di1,2,3-triazole chelator and radiolabeled with [99mTc(CO)3](+).
Ferro-Flores and co-workers synthesized new 99mTc(CO)3triazole-Lys3-bombesin analogue 17 by click chemistry and
found it to have promising characteristics as an effective radiopharmaceutical for the diagnosis of GRP receptor overexpressing tumors.[78]
The progesterone-triazole derivatives 18 were synthesized
and radiolabeled with the [99mTc(CO)3ACHTUNGRE(H2O)3] + precursor in
95 % radiochemical yield.[79] In vitro studies carried out in
MCF7 cells indicated binding to the extent of 30 %. Insignificant binding of the 99mTc(CO)3-progesterone triazole com-
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1,2,3-Triazoles as Pharmacophores
plex was observed with nonspecific cell lines such as HT-29.
Preliminary biodistribution studies in female Swiss mice
showed favorable uptake and retention in the uterus but
high uptake in blood. These observations provide insight towards envisaging alternate synthetic modification of the progesterone molecule to achieve the desired receptor specificity.
The amide bond of ceramide was replaced by the non-hydrolyzable 1,2,3-triazole functionality (19 and 20). Click
chemistry was employed by Kim et al. for the synthesis of
the designed analogues.[80] Biological evaluation indicated
that the amide moiety of ceramide is amenable to bioisosteric substitution with the triazole moiety. Some of the analogues were more potent than C2-ceramide as cytotoxic
agents, and the observed cytotoxicity was possibly mediated
through the induction of apoptosis.
A facile and highly efficient method for the regioselective
synthesis of 1,4-disubstituted 1,2,3-triazoles (b-keto 1,2,3-triazoles) in excellent yields by in situ generated b-ketoazides
and terminal alkynes through CuI-catalyzed 1,3-dipolar cycloaddition was described[81] by Vantikommu and his coworkers. The synthesized compounds 21 were screened for
their cytotoxicity in A549 (lung cancer), HT-29 (colon
cancer), and Hela (cervical cancer) by using an MIT assay
that exhibited significant cytotoxicity at modest doses.
dos Anjos and his group achieved convergent synthesis of
an unusual class of compounds
by the copper-catalyzed [3+2]
cycloaddition
reaction
of
2,3,4,6-tetra-O-acetyl-b-d-glucopyranosyl azide with propynyl
3-[3-(aryl)-1,2,4-oxadiazol-5-yl]
propionates.[82] All the products
(22) presented weak cytotoxic
activity (22–25 % cell-growth
inhibition against NCl-H-292
(lung carcinoma) and HEp-2
(larynx carcinoma)).
TSP50, a breast-cancer-sensitive protease, was immobilized by Shi et al. onto fibers electrospun from biodegradable polymer by introducing propargyl groups into the polymer chains, thus azidizing the
TSP50 and performing the click reaction between the propargyl groups and the azido groups.[83] The TSP50-immobilized fibers were found to specifically recognize and combine anti-TSP50 from a mixed solution that contained as
high as 104 times of other proteins. This is a universal
method to immobilize proteins on biodegradable polymer
substrates.
Synthesis, cytotoxicity, and liposome preparation of 28acetylenic betulin derivatives was carried out by Csuk
et al.[84] The compounds were screened for their antitumor
activity in a panel of 15 human cancer cell lines in sulforhodamine B (SRB) assay. Several compounds showed noteworthy antitumor activity. Encapsulation of these compounds into liposomes resulted in increased cytotoxicity.
Chem. Asian J. 2011, 6, 2696 – 2718
The results from trypan-blue test and from DNA laddering
provided evidence for an apoptotic cell death.
A series of N-[(1-benzyl-1 H-1,2,3-triazol-4-yl)methyl]arylamides was synthesized[85] by Stefely and co-workers and afforded inhibitors of cancer cell growth. One of the compounds exhibited an IC50 of 46 nm against MCF-7 human
breast tumor cells. Structure–activity relationship studies
demonstrated 1) the importance of meta-phenoxy substitution of the N-1-benzyl group for antiproliferative activity
and 2) tolerance of a variety of heterocyclic substitutions for
the aryl group of the arylamide.
Glycosyl 1,2,3-triazoles with a-d-gluco, b-d-gluco, a-d-galacto,
b-d-galacto,
and
b-2-acetamido-2-deoxygluco
(GlcNAc) stereochemistry were prepared by reaction of the
corresponding azides with vinyl acetate under microwave irradiation.[86] Of the four fungal glycosidases evaluated,
GlcNAc-triazole was found to be hydrolyzed by Talaromyces flavus CCF 2686 b-N-acetylhexosaminidase and was established to act as a strong ligand of rat and human natural
killer cell-activating receptors.
Li et al. reported the synthesis of two novel series of 31,2,3-triazol-1,8-naphthalimides by employing a click reaction.[87] Compounds in one series were found to be more
toxic against MCF-7 cells, whereas those in the other series
were more potent against 7721 cells. In particular, compound 23 (R = H) showed IC50 values of 0.348 and 0.258 mm
against cell lines MCF-7 and 7721, respectively. Due to the
phenyl group linked to 1,2,3-triazole, compound 23 (R = Ph)
not only showed higher DNA affinity but also more efficient
DNA damaging ability than compound 23 (R = H).
The tubulin/microtubule system plays a key role during
mitosis and disturbing its dynamic equilibrium can prevent
cell division and induce apoptosis. Up to now, most of the
known microtubule-stabilizing antitubulin agents, such as
paclitaxel (taxol), discodermolide, or epothilones, are characterized by very complex structure, and are therefore difficult to synthesize. Manach et al. developed a very simple
and efficient synthetic route to possible taxol substitutes
(24) by a stereoselective b-glycosylation of l-glucurono-glactone followed by a click cycloaddition of aromatic structures, thus providing fast access to a small library of compounds.[88] The molecules were proposed to act as potential
inhibitors of tubulin depolymerization and show cytotoxic
properties.
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4-Aryl-5-cyano-2 H-1,2,3-triazoles (25) which bear a variety of groups at the 4-position of phenyl were synthesized by
Cheng et al. and investigated their bioactivity as HER2 tyrosine kinase inhibitors.[89] 5-Cyano-2 H-1,2,3-triazole derivatives were found to be the most active in inhibiting the
growth of the HER2 tyrosine kinase phosphorylation in
breast cancer MDA-MB-453 cells.
4.2. HIV Protease Inhibitors
The global AIDS epidemic has claimed the lives of more
than 20 million people since 1981. HIV-1 protease (HIV-1Pr) has been recognized as an important target for inhibition of viral replication. The alarming rate at which strains
of HIV-1 are becoming resistant to the currently available
drugs and their combinations underscores the urgent need
for new, broad-spectrum protease inhibitors that are effective against the new mutants as well as the wild-type viruses.
A focused library of 1,4-disubstituted-1,2,3-triazoles (26)
was synthesized by Whiting et al. by using azide-containing
fragments with a diverse array of functionalized alkyne-containing building blocks by using a click reaction.[90] These
compounds exhibited high binding efficiency to human immunodeficiency virus type-1 protease (HIV-1-Pr). Fictionalization of the triazoles at the 5-position gave a series of compounds with increased activity and exhibited Ki values as
low as 8 nm.
Synthesis of carbocyclic and phosphonocarbocyclic analogues of ribavirin (27), an anti-HCV inhibitor, are described by Saito et al.[91] These compounds were evaluated
not only against HCV, but also against other important viruses, to determine their spectrum of antiviral activity. Some
of the compounds displayed moderate IC50 against HIV-1.
Mohapatra and his group described a one-pot synthesis of
novel tetracyclic scaffolds that incorporated a fusion of proline-1,2,3-triazole ring with [1,4]-benzodiazepin-8ACHTUNGRE(4 H)-one
ring systems.[92] The synthesized compounds 28 were evaluated against protease inhibitors and some of them showed
good serine protease inhibition activity.
Reaction of 3-alkynylmethylcoumarins with azidothymidine (AZT) in the presence of a CuI catalyst afforded a
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series of 1,2,3-triazole-containing products 29, as potential
dual-action HIV-1 protease and non-nucleoside reverse transcriptase inhibitors, and as scaffold for further structural
elaboration.[93]
The synthesis of several 1-benzyl-1 H-1,2,3-triazoles attached to different carbohydrate templates has been carried
out by da Silva and his group and studied their in vitro inhibitory profile against HIV-1 reverse transcriptase.[94] Some
of the compounds inhibited the HIV-1 reverse transcriptase
catalytic activity with cytotoxicity lower than AZT and syncytium inducing (SI) higher than DDC and DDI. They
found that the 1,2,3-triazole compounds presented more lipophilicity and higher molecular volume and weight than the
antivirals studied. This suggested that these features not
only contribute for new interactions with the HIV-RT but
also influence the specificity and consequently the low cytoxicity profile of these compounds.
4.3. Antituberculosis
Tuberculosis (TB) is one of the
leading causes of mortality. The
current World Health Organization (WHO)-approved treatment for TB, known as directly
observed therapy short-course
(DOTS), involves a three- or
four-drug regimen that comprises isoniazid, rifampin, pyrazinamide, and/or ethambutol for a
minimum of six months. Although these first-line agents
remain useful in treating susceptible Mycobacterium tuberculosis strains, the emergence of
multidrug-resistant tuberculosis demands the development
of new drugs.
Somu et al. reported the synthesis of a rationally designed
nucleoside (30).[95] This compound was found to be inhibitor
of Mycobacterium tuberculosis that disrupts siderophore biosynthesis. The activity is due to inhibition of the adenylateforming enzyme MbtA, which is involved in biosynthesis of
the mycobactins.
Two series of 1,2,3-triazole compounds with antimycobacterial profile were reported by Costa et al.[96] The in vitro
anti-tuberculosis screening of these series showed that the
triazole-4-carbaldehyde derivatives (31 A) were more effective than the 4-difluoromethyl derivatives (31 B). A structure–activity relationship (SAR) study indicated the importance of hydrogen-bond acceptor subunit, its position in the
aromatic ring, the planarity of triazole and phenyl rings, and
uniform HOMO coefficient distribution in these compounds
for the anti-tubercular activity.
Tripathi and his group carried out the synthesis of 1-(2,3dihydrobenzofuran-2-yl-methyl [1,2,3]-triazoles (32) and
studied their antitubercular activity against Mycobacterium
tuberculosis H37Rv.[97] Most of the compounds exhibited an-
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with polyprenol–phosphate–mannose (PPM)-dependent R(1,6)-mannosyltransferases showed the highest activity
(IC50 = 0.14–0.22 mm). It was proposed that 1,4-disubstituted
triazole ring spacers contribute substantially to the overall
length of these non-natural oligomannosides. The presence
of a non-natural C-glycosidic linkage and triazole linker in
oligomannosides did not perturb their molecular recognition
properties toward these mycobacterial R-(1,6)- mannosyltransferases.
4.4. Antifungal and Antibacterials
titubercular activities with minimum inhibitory concentration (MIC) values ranging from 12.5 to 3.12 mg mL 1.
Dabak and co-workers studied antitubercular activity of
4-acyl-1 H-1,2,3-triazole derivatives, which were synthesized
by condensation of a-diazo-b-oxoaldehyde compounds with
different amines.[98] 5-Azido-5-deoxyxylo-, ribo-, and arabinofuranoses (33) were found to show antitubercular activity
against Mycobacterium tuberculosis H37Rv.[99] The best
compound displayed antitubercular activity with MIC
12.5 mg mL 1.
A series of 1,2,3-triazole derivatives of 5’-O-[N-(salicyl)sulfamoyl]adenosine (34) (Sal-AMS) was synthesized as inhibitors of aryl acid adenylating enzymes (AAAE) involved
in siderophore biosynthesis by Mycobacterium tuberculosis.[100] Structure–activity relationships revealed remarkable
ability to tolerate a wide range of substituents at the 4-position of the triazole moiety, and the majority of the compounds possessed subnanomolar activity.
On the basis of promising results of the preliminary study,
novel H37Rv strain inhibitors with fluorine and 1,2,3-triazole containing benzimidazoles (35) for the treatment of tuberculosis were disclosed by Gill et al.[101]
A modular approach has been established by Dondoni
et al. for the preparation of a set of C-oligomannosides (36)
that feature a 1,2,3-triazole ring as the interglycosidic linker
as Mycobacterium tuberculosis cell wall synthase inhibitors.[102] The biological experiments indicated that triazoletethered oligomannosides (TOM) (36) endowed with the
optimal chain lengths (36 A and 36 B) for the interaction
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The incidence of life-threatening fungal infections has tremendously increased in the last two decades due to greater
use of immunosuppressive drugs, prolonged use of broadspectrum antibiotics, widespread use of indwelling catheters,
and also in cancer and AIDS patients. The presently marketed antifungal and antibacterial drugs are either highly
toxic or becoming ineffective due to the appearance of resistant strains. This necessitates continuing research into
new classes of antimicrobial agents. 1,2,3-Triazole-containing
molecules is one of these classes.
We designed and synthesized fluconazole/bile acid conjugates at C3 and C24 positions of bile acids under microwave-assisted CuI-catalyzed cycloaddition reaction.[103] This
reaction gave fluconazole/bile acid conjugates, linked with
1,4-disubstituted 1,2,3-triazole regioselectively, in excellent
yield and in less reaction time. These new molecules showed
very good antifungal activity against Candida species with
MIC values ranging from 3.12 to 6.25 mg mL 1. It was
thought that in this biological activity, the bile acid part acts
as a drug carrier and the fluconazole part acts as an inhibitor of 14a-demethylase enzymes in the fungal cell. We also
synthesized fluconazole-based novel mimics 37 and 38 that
contained 1,2,3-triazole with or without substitution at C4.
Some of the compounds were found to be more potent
against Candida fungal pathogens than control drugs fluconazole and amphotericin B. These molecules were evaluated
in vitro against Candida albicans intravenous challenge in
Swiss mice, and antiproliferative activities were tested
against human hepatocellular carcinoma Hep3B and human
epithelial carcinoma A431. It was found that a compound
with a long alkyl chain resulted in 97.4 % reduction in
fungal load in mice and did not show any profound proliferative effect at lower dosage (0.001 mg mL 1).
Synthesis of novel 1,2,3-triazole-linked b-lactam–bile acid
conjugates 39 and some dimeric compounds (40) by 1,3-dipolar cycloaddition reaction of azido b-lactam and terminal
alkyne of bile acids by using a click reaction was also reported by us.[104] Most of the compounds exhibited significant antifungal and moderate antibacterial activity against all the
tested strains. One of the compounds showed very good antifungal activity with an MIC value of 16 mg mL 1 against C.
albicans and 8 mg mL 1 against B. poitrasii.
Chaudhary et al. synthesized several novel 1,4-disubstituted-1,2,3-triazolyluridine derivatives (41) by means of a click
chemistry approach, most of which showed significant anti-
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fungal activity.[105] One of the compounds showed potent antifungal activity against C. neoformans with an MIC of
8 mg mL 1 (0.018 mg mL 1 for Fluconazole). Some other compounds in the series showed antifungal activity with MIC
values of 24–32 mg mL 1 (0.048–0.067 mg mL 1 for Nikkomycin) against C. albicans. These compounds were proposed as
leads chitin synthase inhibitors for further modifications.
They also have potential for applications in health care and
in agriculture.
Sangshetti and Shinde developed a new, convenient,
simple, and efficient method for the synthesis of a novel
series of 3-[1-(1-substituted piperidin-4-yl)-1 H-1,2,3-triazol4-yl]-5,6-diphenyl-1,2,4-triazines (42) by using ZrOCl2·8 H2O
as a catalyst.[106] A novel series of 1,2,3-triazole compounds
that possessed a 1,2,4-oxadiazole ring (43) was also efficiently synthesized by these authors.[107] The SAR for the series
has been developed by comparing their MIC values with miconazole and fluconazole. Some of the synthesized com-
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pounds were found to be as active as or more active than
miconazole and comparable to that of fluconazole.
A quinoline skeleton is often used for the design of many
synthetic compounds with diverse pharmaceutical properties. Kategaonkar and co-workers reported antimicrobial activities of new 2-chloro-3-[(4-phenyl-1 H-1,2,3-triazol-1-yl)methyl]quinoline derivatives (44) against a large number of
fungal and bacterial strains.[108]
Leishmaniasis is caused by several species of protozoan
parasites transmitted by the bite of the female phlebotomine
sand fly. Classified as an extremely neglected disease, leishmaniasis is still present as an additional difficulty in the long
and inefficient treatment that is dependent on old and
highly toxic drugs like azole antifungals. To find new drugs
with antileishmanial activity,
Ferreira et al. synthesized new
imidazole and triazole compounds and evaluated them
against promastigote forms of
Leishmania
amazonensis.[109]
The results showed that the introduction of the difluoromethylene moieties (45) turned
the inactive carbaldehydes into
active antileishmanial compounds with IC50 below 3.0 mm.
This type of compounds also
showed antituberculosis activity
(see compound 32).
A series of sugar modules that bear two kinds of reactive
handles (alkynyl and azide) was enzymatically synthesized
from unprotected sugars in one step. Sequential one-pot
procedures for enzymatic glycosylation and azide–alkyne cycloaddition were developed, thus giving access to triazole-
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1,2,3-Triazoles as Pharmacophores
containing glycosides 46.[110] The activities of triazole glycosides detected in subsequent bioassays showed that this procedure is a feasible approach to the development of antifungal drugs.
Reck et al. reported synthesis and biological evaluation of
novel oxazolidinones that bear a 4-substituted triazole
moiety (47).[111] Vinylsulfone and tosylhydrazone reagents
were found to provide good selective access to this class of
compounds, in addition to the copper(I)-catalyzed ligation
of azides with alkynes. It was found that compounds that
bear a small substituent, linked though the sp or sp3 center
to the 4-position of the triazole moiety, were potent antibacterials against Gram-positive bacteria, and many of these
compounds were found to be inhibitors of monoamine oxidase A (MAO-A). These authors also synthesized new analogues of oxazolidinones that bear a (pyridin-3-yl)phenyl
moiety with acyclic substituents on the pyridyl moiety (compound 48),[112] thus exhibiting excellent activity against
Gram-positive pathogens, including linezolid-resistant Streptococcus pneumoniae.
A series of 5-(4-methyl-1,2,3triazole)methyl oxazolidinones
49 was synthesized by Phillips
and co-workers.[113] Most of the
compounds
demonstrated
strong in vitro antibacterial activity against susceptible and resistant Gram-positive pathogenic bacteria. Antibacterial activity varied with substitutions at
the phenyl C4 position, with
bulky alkyl carbonyl and alkoxycarbonyl substitutions on the
piperazine N4 being detrimental to antibacterial activity. The
presence of the 4-methyl-1,2,3triazole moiety in the acyl piperazine-containing analogues
resulted in increased protein
binding and decreased antibacterial activity particularly against Streptococcus pneumoniae
strains.
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Novel antibacterial biaryl oxazolidinones that bear an
aza-, an oxa-, or a thiabicycloACHTUNGRE[3.1.0]hex-6-yl ring systems
were synthesized by Komine et al.[114] Most of the synthesized biaryl bicycloACHTUNGRE[3.1.0]hex-6-yl oxazolidinones showed
good antibacterial activity against Gram-positive and Gramnegative bacteria.
Oxazolidinones that contain a benzodioxin moiety (50)
were synthesized by Ebners
group and their antimicrobial
activity was tested.[115] The MIC
against S. aureus was determined to be 2–3 mg mL 1 for
one of the compounds. This
compound has similar antimicrobial activity against S. aureus
as linezolid, (4 mg mL 1). It appears that the benzodioxin ring
system does not alter the activity of the oxazolidinone by replacement of an amide with
1,2,3-triazole.
Chen et al. synthesized compounds for development of pharmaceutical agents against
endotoxemia and septic shock.[116] They designed and synthesized nonpeptide, calixarene-based helix/sheet topomimetics that mimic the folded conformations of these peptides in their molecular dimensions, amphipathic surface
topology, and compositional properties. From a small library
of topomimetics, several compounds were identified that
neutralize lipopolysaccharide (LPS) in the 10 8 m range, thus
making these compounds as effective a bactericidal/permeability-increasing protein as polymyxin B. Some of the triazole-linked primary amine calixarene derivatives (51) were
found to exhibit excellent activity compared with that of the
t-butyloxycarbonyl (Boc)-protected derivative at 5–10 6 m.
A facile synthetic protocol for the production of neomycin B derivatives (52) with various modifications at the 5’-
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position was developed by Zhang and co-workers.[117] The
structure–activity relationship against aminoglycoside resistant bacteria equipped with various aminoglycoside-modifying enzymes (AMEs) was investigated. Several derivatives
showed enhanced antibacterial activity comparable to that
of the parent neomycin. When these synthetic neomycin derivatives were tested against other human pathogens, some
leads exhibited prominent activity against methicillin-resistant Staphylococcus aureus (MRSA) as well as vancomycinresistant enterococci (VRE) that are known to exert a high
level of resistance against clinically used aminoglycosides.
Modification of old drugs was suggested to provide new
leads.
Bakunov and co-workers synthesized dicationic triazoles
(53) by the Pinner method from the corresponding dinitriles
through a click reaction.[118] Type and position of the cationic moieties as well as nature of the aromatic substituents, influenced the in vitro antiprotozoal activities of these compounds against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, and their cytotoxicity for mammalian cells. A few congeners displayed antitrypanosomal IC50 values below 10 nm. Most of the dications
were more potent against P. falciparum than pentamidine
(IC50 = 58 nm), and some analogues were more active than
artemisinin (IC50 = 6 nm).
Synthesis and biological evaluation of two novel series of
natural-product-like hybrids that contained thiolactone-chalcone and isatin-chalcone scaffolds (54 and 55) was described
by Hans et al.[119] Results for the 36-member b-amino alcohol triazole library showed that the thiolactone-chalcones,
with IC50 ranging from 0.68 to 6.08 mm, were more active
against W2 strain Plasmodium falciparum than the isatinchalcones with IC50 of 14.9 mm
The synthesis of a library of nonactic acid-derived triazoloamide derivatives (56) and their evaluation as antimicrobial agents was described by Luesse et al.[120]
Sumangala and co-workers synthesized a 1,2,3-triazolecontaining quinoline moiety (57).[121] They studied their anti-
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microbial and antifungal activity by using cyclo-piroxolamine as standard antifungal agent. Investigation of the
structure–activity relationships revealed that the nature of
the substituent on the 4-position of the triazole ring influences the antimicrobial activity. Most of the newly synthesized
compounds showed significant antimicrobial activity at a
concentration of 6.25 mg mL 1.
Two substituted 1,2,3-triazoles such as N-(1-arylmethylene)-1-[8-(trifluoromethyl)quinolin-4-yl]-5-methyl-1 H-1,2,3triazole-4-carbohydrazides and 1-aryl-4-{1-[8-(trifluoromethyl)quinolin-4-yl]-5-methyl-1 H-1,2,3-triazol-4-yl}prop-2-en1-ones showed good antimicrobial activity.[122] Thomas and
co-workers reported antimicrobial activities of new quinoline derivatives (58) with a 1,2,3-triazole moiety.[123]
The synthesis and antimicrobial evaluation of glycal-derived novel tetrahydrofuran 1,2,3-triazoles (59 and 60) has
been reported by Reddy et al.[124] The most active molecule
showed antibacterial and antifungal activities with a MIC
value of 12.5 mg mL 1.
The pyranonaphthoquinone family of antibiotics displays
a wide range biological activity with medicinal potential.
One subclass within this family, the nanaomycins, are of particular interest due to their relatively simple, unique structure and biological activity, thus rendering them attractive
lead compounds. A series of triazole analogues of the nanaomycin (61) family of antibiotics was prepared by Rathwell et al. by using a click dipolar cycloaddition of a naphthalene azide to various alkynes, followed by oxidation to
the desired pyranonaphthoquinones.[125]
4.5. Miscellaneous
1-(5-{[(2R,3S)-2-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholin-4-yl]methyl}-2H1,2,3-triazo-l,4-yl)-N,N-dimethylmethanamine hydrochloride
(62) was found to be an orally active, h-NK1 receptor antagonist with a long central duration of action and high solubility in water (> 100 mg mL 1), which is due to the incorporation of the 1,2,3-triazol-4-yl
group. The construction of the
5-dimethylaminomethyl 1,2,3triazol-4-yl unit was accomplished by thermal rearrangement of a propargylic azide in
the presence of dimethylamine.[126] Compound 62 was
found to be highly effective in
preclinical tests for emesis and
depression.
Stensbo and co-workers reported the synthesis and biological activity of 1-hydroxy azole
derivatives.[127] As analogues of
the receptor agonist (R,S)-2amino-3-(3-hydroxy-5-methyl-4isoxazolyl)propionic
acid
(AMPA), some of these com-
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pounds that contain a 1,2,3-triazole group exhibited high affinity for [3H]-AMPA receptor binding sites.
The synthesis of a new class of 5-heteroaryl-substituted 1(4-fluorophenyl)-3-(4-piperidinyl)-1 H-indoles (63), as highly
selective and potentially CNS-active m1-adrenoceptor antagonists, has been reported by Balle et al.[128] Structure–activity
relationships of the 5-heteroaryl substituents and the substituents on the piperidine nitrogen atom were optimized
with respect to their affinity for a1-adrenoceptors and selectivity in respect to dopamine (D1–4) and serotonin (5-HT1A,1B
and 5-HT2A,2C) receptors.
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Roppe et al. synthesized heteroaryl azoles (64) that exhibit anxiolytic activity.[129] Though the tetrazole compounds
showed excellent activity, some of the 1,2,3-triazole analogues synthesized using click chemistry exhibited moderate
activity and good oral bioavailability in rats.
Pryde and co-workers synthesized a number of compounds as endopeptidase (NEP) inhibitors (the enzyme responsible for female sexual arousal disorder).[130] One of the
compounds (65) that contains the 1,2,3-triazole exhibited appreciable potency (82 nm) against NEP.
Recently, researchers have used acetylcholinesterase
(AChE) as a reaction vessel to synthesize its own inhibitors.
3,8-Diamino-6-phenyl-5-[6-(1-{2-[(1,2,3,4-tetrahydro-9-acridinyl)amino]ethyl}-1 H-1,2,3-triazol-5-yl)hexyl]phenanthridinium (66), can be synthesized exclusively inside the AChE
gorge. It was found to be the highest-known affinity-reversible organic inhibitor of acetylcholinesterase (dissociation
constant Kd is 77–410 fm depending on the AChE source).
Senapati and co-workers carried out quantum mechanical/
molecular mechanical (QM/MM) calculations, molecular dynamics (MD), and targeted molecular dynamics (TMD)
studies to find out why this compound is the sole product in
the AChE environment.[131]
Click chemistry was explored by Cosyn et al. for the synthesis of two series of 2-(1,2,3-triazolyl)adenosine derivatives (67 and 68).[132] Binding affinity at the human A1, A2A,
and A3ARs (adenosine receptors) and relative efficacy at
the A3AR were determined. Some triazol-1-yl analogues exhibited A3AR affinity in the low nanomolar range, a high
ratio of A3/A2A selectivity, and a high A3/A1 ratio. The 1,2,3triazol-4-yl regiomers typically showed decreased A3AR affinity.
Lolk and co-workers synthesized various pleuromutilin
conjugates (69) with different nucleoside fragments as sidechain extensions by a click chemistry protocol.[133] Binding
was assessed by chemical footprinting of nucleotide U2506
in 23S rRNA. All the conjugates were found to bind to the
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peptidyl transferase center with varying degrees, thus reflecting their binding affinity. The side-chain extensions also
showed various protections at position U2585. Docking
studies of the conjugates with the highest affinities supported the conclusion that, despite the various conjugations, the
pleuomutilin skeleton binds in the same binding pocket. The
conjugated 1,2,3-triazole moiety was found to be well accommodated, and the nucleobases were placed in different
pockets in the 50S ribosomal subunit. The derivative that
showed the highest affinity and significantly better binding
than pleuromutilin itself contains an adenine-9-ylpropylene
triazole conjugate to pleuromutilin C-22.
Radiolabeled peptides, which were utilized for in vitro
imaging of a variety of cell surface receptors, were reported
by Hausner et al.[134] For applications in positron emission
tomography (PET) by using [18F] fluorine, peptides were radiolabeled by means of a prosthetic group approach. One of
the peptides that included a 1,2,3-triazole moiety with an
[18F]n-fluoropropyl side chain (70) exhibited a noticeable
effect on pharmacokinetics.
An efficient and convenient chemical and radiochemical
synthesis of two 4-substituted 1,2,3-triazolyl b-d-galactopyranosides (71) was developed by Celen et al.[135] The compounds were synthesized in good yields by using a click reaction between acetylated b-galactosyl azide and the corresponding terminal alkynes. Radiolabeling produced two
[11C]-labeled compounds in amounts and purity suitable for
PET studies. Both tracers were very stable in vitro. Cell
uptake experiments in LacZ expressing and control 293T
cells, revealed an increased cell uptake for the naphthylic
tracer compared to the phenylic triazole. Development of
lipophilic 11C- and 18F-labeled b-galactosyl triazoles with a
higher binding affinity for LacZ was proposed to lead to
higher cell uptake ratios and better in vitro imaging contrasts.
Fujinaga et al. described the synthesis and characterization of a PET ligand [18F] (72) for imaging mGluR1 in the
rat brain.[136] This compound was synthesized by [18F] fluorination of the bromo precursor with [18F] at high and reproducible radiochemical yields. It exhibited in vitro and in
vivo binding with mGluR1 in the brain regions such as the
cerebellum, thus suggesting its usefulness.
Discovery of a new class of macrocyclic histone deacetylase inhibitors (HDACi) based on macrolide antibiotics skeletons (73) was reported by Oyelere et al.[137] SAR studies revealed that these compounds displayed both linker-lengthand macrolide-type-dependent HDAC inhibition activities
with IC50 in the nanomolar range. These nonpeptide macrocyclic HDACi were also found to be more selective against
HDACs 1 and 2 relative to HDAC 8.
Cox et al. synthesized dual orexin receptor antagonists
[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2 H-1,2,3-triazol-2-yl)phenyl] methanone (74) for the treatment of insomnia.[138]
A series of benzoxazinones with small heterocyclic rings
has led to fused tricyclic benzoxazines (75), which are
potent 5-HT1A/B/D receptor antagonists with and without con-
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comitant human serotonin transporter (hSerT) activity. A
number of new hetero-tricyclic ring systems were synthesized by Bromidge and co-workers, such as fused imidazolo,
triazolo, and tetrazolo-benzoxazines, to study the effect on
the binding affinity to the receptor.[139]
Methods for a rapid and efficient synthesis of new 3-m[1,2,3]triazol-3-deoxythymidine analogues (76) from AZT
under Huisgen conditions was described by Lin et al.[140] The
new analogues showed higher efficiencies (Km/Vmax values)
in all cases with Ureaplasma parvum thimidine kinase
(UpTK) than with human cytosolic thymidine kinase
(hTK1). Structural models of UpTK and hTK1 were constructed and used to explain the kinetic results. Two different binding modes of the nucleosides within the active sites
of both enzymes were suggested, with one predominating in
the bacterial enzyme and the other in hTK1.
In an effort to increase the potency and selectivity of previously identified substrate-based inhibitors of mitochondrial thymidine kinase 2 (TK-2), Peocke and co-workers described the synthesis of thymidine analogues that contained
4- or 5-substituted 1,2,3-triazol-1-yl substituent at the 3’-position of the 2’-deoxyribofuranosyl ring.[141] These analogues
were prepared by Cu- and Ru-catalyzed cycloadditions of
3’-azido-3’-deoxythymidine and the appropriate alkynes,
which produced 1,4- and 1,5-triazoles, respectively. Selected
analogues exhibited nanomolar inhibitory activity for TK-2,
while virtually not affecting the TK-1 counterpart. Enzyme
kinetics indicated a competitive and uncompetitive inhibition profile against thymidine and the cosubstrate ATP, respectively.
Wuest et al. prepared a series of compounds based on a
central 1,2,3-triazole scaffold with two aryl substituents as a
novel class of COX-2 inhibitors (77).[142] Compounds with a
vicinal diaryl substitution pattern showed more potent
COX-2 inhibition relative to their corresponding 1,3-diarylsubstituted counterparts. In both the series, compounds that
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1,2,3-Triazoles as Pharmacophores
possessed an electron-withdrawing group (Cl and F) at the
para position of one of the aryl rings, displayed higher
COX-2 inhibition potency than that of compounds that contained electron-donating groups (Me, OMe, NMe2).
The 1,2,3-triazole ring is suitable as a surface-recognition
cap-group-linking moiety in suberoylanilide hydroxamic
acidlike (SAHA-like) histone deacetylase (HDAC) inhibitors. The structure–activity relationship of the resulting triazole-linked hydroxamates displayed a cap-group-dependent
preference for either five- or six-methylene spacer groups.
Chen et al. identified compounds (78), that were several
folds more potent than SAHA.[143] A subset of these compounds also inhibited the proliferation of DU-145 cells. Due
to their anticipated resistance to intracellular peptidases,
these triazole-linked HDAC inhibitors were expected to display improved in vitro activity relative to the common
amide-based inhibitors.
Lin et al. prepared dimeric acetylated and benzoylated bC-aryl gluco- and galactopyranosides (79) by Huisgen 1,3-dipolar cycloaddition reaction between 6-azido-b-C-aryl glycosides and dipropargyl isophthalate in good yields.[144] Mild
oxidation converted b-C-glycosyl-1,4-dimethoxy benzenes or
naphthalenes into the corresponding b-C-glycosyl 1,4-benzoquinone or 1,4-naphthoquinone derivatives. Benzoylated
glucosyl and galactosyl dimers that contained a 1,4-dimethoxybenzene or 1,4-benzoquinone moiety showed submicromolar inhibitory activity (IC50 = 0.62–0.88 mm) against
PTP1B, with no significant difference between gluco and
galacto derivatives.
Neves et al. described the synthesis and pharmacological
evaluation of N-phenylpiperazine heteroaryl azole derivatives (80) as potential multitarget drugs and confirmed the
potential usefulness of this molecular scaffold for the devel-
New biotinylated dopamine (81) that contained a photolabile 8-quinolinyl benzenesulfonate moiety (BDQB) has
been reported by Aoki and co-workers.[146] This photocleavable biotin linker was easily incorporated into small molecules by using Huisgen 1,3-dipolar cycloaddition. Complexation of BDQB with avidins was examined. An anti-dopamine antibody (IgG1) and the photorelease of dopamineIgG1 complexes by enzyme-linked immunosorbent assay
(ELISA) was confirmed by Western blot. These methods
were found to provide effective strategies for the recovery
of intact ligand-receptor complexes under mild conditions
without the need for damaging chemical reagents. Moreover, the photolysis of BDQB proceeded cleanly to give the
corresponding quinolinols and sulfonates, which would be
advantageous over the previous chemically cleavable biotin
linker.
Alam et al. synthesized a series of 4,5-disubstituted 1phenyl-1 H-1,2,3-triazoles (82) and examined their antagonist potencies (affinities) in human b3 and a1b2g2 GABA receptors.[147] These compounds exhibited high affinity for
both b3 and a1b2g2 receptors. Most of the analogues were
more potent in b3 receptors than in a1b2g2 receptors.
Shus group reported the regioselective synthesis of a
series of 4-alkoxycarbonyl-1,5-diaryl-1,2,3-triazoles (83) by
using click chemistry, and the compounds were evaluated
for binding affinity at CB1 cannabinoid receptors.[148]
Among the synthesized compounds n-propyl ester (Ki =
4.6 nm) and phenyl ester (Ki = 11 nm) exhibited the most
potent affinity.
A straightforward synthesis of a novel class of triazoloacyclic nucleoside phosphonates (84) was designed by Elayadi
et al.[149] Preliminary structure–activity relationship evaluation of these compounds suggested this scaffold to have po-
opment of new second-generation antipsychotic drugs.[145]
Among the compounds prepared, LASSBio-579 (80; W =
Cl, Y = H) and LASSBio-664 (80; W = F Y = H) exhibited
the highest affinity for binding to the D2-like and 5-HT1A
receptors. In mice, these derivatives demonstrated potential
for treating positive symptoms of schizophrenia.
tential for further optimization as selective inhibitors of
HCV replication.
Todoroki et al. enlarged the uniconazole (UNI) molecule
to find specific inhibitors of abscisic acid (ABA) 80-hydroxylase and synthesized various UNI derivatives (85) that
were substituted with hydrophilic and hydrophobic groups
by replacing the 4-chloro functionality.[150] Considering its
Chem. Asian J. 2011, 6, 2696 – 2718
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potency in ABA 80-hydroxylase inhibition, its small effect
on seedling growth, and ease of application, the UNI derivative that contained C4 alkyltriazole-UT4 was found to be
the best inhibitor of ABA 80-hydroxylase.
The synthesis of various 1-(4-deoxy-4-fluoro-b-d-xylopyranosyl)-1,2,3-triazole derivatives (86) has been reported by
Tsuzukis group.[151] Among these derivatives some derivatives were found to be very good inhibitors of glycosaminoglycan biosynthesis.
influenza replications, even though they were somewhat less
potent in neuraminidase inhibition than the monomeric zanamivir.
The conjugation of lipid moieties through click chemistry
potentiated the cellular uptake of oligonucleotides (89) and
allowed their intracellular delivery.[155] Furthermore, these
nontoxic lipid conjugates efficiently inhibited hepatitis C
virus internal ribosome entry site (IRES)-mediated translation in human hepatic Huh7 cells. The biological activity of
Brockunier et al. identified a new series of human b3adrenergic receptor agonists that contained 1,2,3-triazoles as
heterocyclic urea replacements, which showed improved
oral bioavailability while maintaining the potency, selectivity, and in vitro efficacy.[152] In particular, 4-trifluromethylbenzyl analogue 87 was found to be an exceptionally selective human b3 agonist (b3 EC50 = 3.1 nm; with 6500- and
1500-fold selectivity over binding to b1 and b2 receptors, respectively). When administered intravenously to rhesus
monkeys, this analogue elicited a lipolytic response at low
dosage with minimal effects on heart rate. The 25 % oral
bioavailability of this compound in dogs was a marked improvement over the low bioavailability of acyclic and cyclic
urea.
An efficient strategy for the fast construction of a large library of 1,4-disustituted 1,2,3-triazoles was developed by Jia
and Zhu by using click chemistry.[153] The fingerprint of inhibitory activity toward monoamine oxidase (MAO)-A/B
against this library was obtained, and four hit compounds
were identified as selective inhibitors toward MAO-A.
The synergistic effect of zanamivir–porphyrin conjugates
on inhibition of neuraminidase and inactivation of influenza
virus was studied by Wen et al.[154] These compounds (88)
were found to be 10 to 100 times more potent in inhibiting
these lipid-conjugated oligonucleotides was not affected by
the presence of serum.
The accumulation of b-amyloid aggregates (Ab) in the
brain is linked to the pathogenesis of Alzheimers disease
(AD). Qu et al. reported a novel approach for producing
1,4-diphenyltriazoles as probes for targeting Ab aggregates
in the brain.[156] A series of substituted tricyclic 1,4-diphenyltriazoles (90) that showed excellent binding affinities to Ab
aggregates (Ki = 4–30 nm) were conveniently assembled by
click chemistry. Two radioiodinated probes [125I] and two radiofluorinated probes [18F] exhibited moderate lipophilicities
and showed excellent initial brain penetrations and fast
washouts from the normal mouse brain.
Enynes of type 91 as long-chain derivatives of the nonaromatic dopamine D3 receptor agonist were synthesized by
Dçrfler et al. by exploiting chemoselective functionalization
of the azido-substituted vinyl triflate.[157] These click chemistry derived triazole analogues behaved as strong partial agonists.
N-Amino-1,2,3-triazole derivatives such as 1-(N-substituted phenylamino)-5-methyl-1 H-[1,2,3]-triazole-4-carboxylic
acid ethyl esters and 1-(4-substituted phenylamino)-5methyl-1 H-[1,2,3]-triazole-4-carboxylic acid hydrazides (92),
exhibited significant antiviral effect on Cantagalo virus rep-
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Chem. Asian J. 2011, 6, 2696 – 2718
1,2,3-Triazoles as Pharmacophores
lication.[158] 1-(4-Fluoro-phenylamino)-5-methyl-1 H-[1,2,3]triazole-4-carboxylic acid hydrazide was found to be the
most active antiviral compound.
Colombano et al. exploited a click reaction to synthesize a
huge library of analogues as nicotinamide phosphoribosyltransferase inhibitors.[159] The most promising compound displayed an IC50 for cytotoxicity in vitro of (3.8 0.3) nm and
an IC50 for nicotinamide adenine dinucleotide (NAD) depletion of (3.0 0.4) nm.
A class of drugs used for treating type-II diabetes mellitus
(T2D), typified by pseudotetrasaccharide acarbose, acts by
inhibiting the R-glucosidase activity present in pancreatic secretions and in the brush border of the small intestine. Ferreirathe et al. reported the synthesis of a series of 4-substituted 1,2,3-triazoles conjugated with sugars, including dxylose, d-galactose, d-allose, and d-ribose.[160] Compounds
were screened for R-glucosidase inhibitory activity using
yeast maltase (MAL12) as a model enzyme. Methyl-2,3-Oisopropylidene-b-d-ribofuranosides, such as the 4-(1-cyclohexenyl)-1,2,3-triazole derivative, were among the most
active compounds, showing up to 25-fold higher inhibitory
potency than the complex oligosaccharide acarbose.
New N-alkylaminocyclitols that bear a 1,2,3-triazole
system (93) at different positions of the alkyl chain were
prepared as potential GCase pharmacological chaperones
by using a click chemistry approach.[161] Among them, compounds with a shorter spacer between the alkyltriazolyl
system and aminocyclitol core were the most active ones as
GCase inhibitors, thereby revealing a determinant effect of
the location of the triazole ring on the activity. SAR data
and computational docking models indicated a correlation
between lipophilicity and enzyme inhibition. Hydrogenbond interaction between the triazole moiety and enzyme
residue Q284 would be precluded in compounds with a
longer spacer between the triazole and the aminocyclitol
core.
A library of novel benzenesulfonamides that contain triazole-tethered phenyl tail moieties (94) were synthesized by
Poulsen et al. by using a CuI-catalyzed 1,3-dipolar cycloaddition reaction between 4-azido benzenesulfonamide and a
panel of variously substituted phenyl acetylenes.[162] These
Chem. Asian J. 2011, 6, 2696 – 2718
compounds were very effective
inhibitors of the human mitochondrial carbonic anhydrase
(CA) isozymes VA and VB and
nanomolar inhibitors of hCA
isozymes II, and micromolarinhibitors of hCA I
Wilkinson et al. synthesized a
series of benzene sulfonamides
that contained triazole-O-glycoside tails (95) for evaluation as
carbonic
anhydrase
inhibitors.[163] These glycoconjugates
were synthesized by the 1,3-dipolar cycloaddition reaction of
4-azidobenzenesulfonamide
with O-propynyl glycosides. Compounds were assessed for
their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA I and II and the tumor-associated isozyme hCA IX (h = human). Against hCA I,
these compounds were either micromolar or low-nanomolar
inhibitors, whereas against hCA II and IX, inhibition was in
the range of 6.8–53 and 9.7–107 nm, respectively. The most
potent inhibitor against hCA IX was the galactose derivative
with acetate protecting groups (Ki = 9.7 nm).
1,2,3-Triazole derivatives (96 and 97) of nor-b-lapachone
were found to be more active than the original quinones,
with IC50/1 d values in the range of 17 to 359 mm against the
infective bloodstream trypomastigote form of Trypanosoma
cruzi, the etiological agent of Chagas disease. These triazole
derivatives of nor-b-lapachone were proposed as interesting
new lead compounds in drug development for Chagas disease.[164]
Gigure et al. described the synthesis of stable galactosides and lactosides as potential Gal-1 and Gal-3 inhibitors
against galectins, which compared well with known inhibitors.[165] The best dimers were bis-lactosides (98), which have
both inhibitory properties of 160 mm.
Copper(I)-catalyzed azide–alkyne cycloaddition reaction
was used to prepare O-acetyl- or O-benzoyl-protected 1-dglycopyranosyl-1,2,3-triazoles of the a- and b-d-glucopyranosyl as well as (b-d-glucohept-2-ulopyranosyl)onic acid derivatives (99 and 100) by Bokor et al.[166] Removal of the
protecting groups according to the Zempln protocol gave
test compounds that were assayed as inhibitors of rabbitmuscle glycogen phosphorylase. The 1-(b-d-glucopyranosyl)1,2,3-triazoles proved to be the best inhibitors among the
three series of compounds that exhibited inhibition constants in the low-micromolar range. The a-d-configured derivatives were almost inefficient, and introduction of
CONH2 group at the anomeric position of the b-d-configured series also resulted in a practical loss of activity.
A novel family of 1-arylsulfonylamino-5-methyl-1 H[1,2,3]-triazole-4-carboxylic acid ethyl esters (101) has been
synthesized by Campos et al. and evaluated for its ability to
neutralize L. muta snake venoms hemolytic activity.[167] All
the compounds were able to neutralize hemolytic property
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FOCUS REVIEWS
of venom. The triazole derivatives were proposed to affect
the L. muta venom phospholipase A2, which is involved in
the hemolytic profile of this snake venom. These compounds
were suggested as prototypes for designing new antiophidian
molecules to improve the current treatment used for L.
muta bites.
1,4-Disubstituted 1,2,3-triazoles were prepared by Ciocoiu
et al. as analogues of GW 501516 and tested for their ability
to increase oleic acid oxidation in human myotubes by using
a high-throughput multiwell assay.[168] Compounds {2-[4-({1[3-fluoro-4-(trifluoromethyl)phenyl]-1 H-1,2,3-triazol-4-yl}methylthio)-2-ethylphenoxy]acetic acid} and {2-[4-({1-[3chloro-4-(trifluoromethoxy)phenyl]-1 H-1,2,3-triazol-4-yl}methylthio)-2-methyl-phenoxy]acetic acid} (102) exhibited
potent agonist activities. These compounds also exhibited
powerful agonist effects for both PPAR a and PPAR s in a
luciferase-based assay and hence were categorized as dual
PPAR agonists.
Tornoe and co-workers synthesized a library of 1,4-disubstituted 1,2,3-triazoles by solid-phase peptide synthesis combined with a regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition between resin-bound alkyne and protected
amino azide.[169] The library was screened for its inhibitory
effect against recombinant cysteine protease, Leishmania
mexicana CPB2.8DeltaCTE, with the best inhibitor displaying a Ki value of 76 nm.
The ever-increasing importance of the role of carbohydrates in biological processes that relate to immunology, virology, and a host of life-threatening diseases has created an
interest in access to specific sugar-hybrid molecules. Rajganesh and his group synthesized O-glycosylated sugar hybrid
compounds (103) that contained 1,2,3-triazole.[170] These
compounds showed weak to moderate antioxidant activities,
with a maximum inhibitory activity of 77.3 %.
A library of a-d- and b-d-glucopyranosyl triazoles (104) was
synthesized by Dedola et al.[171]
The triazole library was assayed
for inhibition of sweet almond
b-glucosidase (GH1) and yeast
a-glucosidase (GH13), which
led to the identification of a set
of glucosidase inhibitors effective in the 100 mm range. The
preference for inhibition of one
enzyme over the other proved
to be dependent on the anomeric configuration of the inhibitor.
Large-conductance, calciumactivated potassium channels
(BKCa or BK channels) are
distributed in both excitable
and non-excitable cells and are
involved in many cellular functions. The vasorelaxing effects
of exogenous BK openers can be a rational basis for the
treatment of hypertension and/or other diseases related to
an impaired contractility of vessels. Triazole-carboxamide
derivatives (105) synthesized by Galderone et al. showed
poor activity as BK-potassium channel activators than their
earlier reported molecules, the reason being the increase of
the steric hindrance of the linker and/or the increase in the
distance between the two aromatic portions, which is deleterious to the interaction with the biological target.[172]
Glycoconjugates of a-tocopherol (106) synthesized by
using click chemistry between a-tocopherol azide and glycoalkynes enhanced water solubility and exhibited radicalscavenging activities comparable to a-tocopherol (107), as
determined by DPPH and lipid peroxidation assay methods.[173]
An amphiphilic PEG–PMPC–PLA (PEG = polyethylene
glycol; PMPC = polymethypropargyloxycarbonyl); PLA =
polylactic
acid)
triblock
biodegradable
copolymer
(Scheme 4) was synthesized by Shi and co-workers.[174] The
copolymer formed three-layer micelles in aqueous solution
with PEG as shell, PMPC as outer core, and PLA as inner
core. Through the propargyl groups on the PMPC layer, hemoglobin molecules were conjugated to the micelles by
means of click chemistry and the micellar diameter in-
Scheme 4. Structures of triblock biodegradable copolymer.
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1,2,3-Triazoles as Pharmacophores
creased to about 150–200 nm. The Hb content in the HCMs
reached as high as 70 wt % and the conjugated hemoglobins
retained their O2-binding ability. Therefore the HCMs prepared were proposed as artificial oxygen carriers.
Conclusion
In conclusion, click chemistry has proven to be a powerful
tool in biomedical research, with applications that range
from combinatorial chemistry and target-templated in vitro
chemistry for lead discovery, to bioconjugation strategies for
proteomics and DNA research. This triazole-forming process by click chemistry promises to accelerate both lead
finding and lead optimization, due, above all, to its great
scope, modular design, and reliance on extremely short sequences of near-perfect reactions. In a short period, click
chemistry has had a dramatic and diverse impact in the area
of drug discovery and development. Research and development in this field are still increasing exponentially.
The versatility of the CuI-catalyzed Huisgen cycloaddition
(click reaction) seems endless, yet we are still in the early
developmental stages of this concept-driven research. Click
processes can be used for the integration and/or linkage of
biomolecules (polyamines, amino acids, and carbohydrates),
drugs, and other functional molecules with each other by
1,2,3-triazole ligation, mainly crafted with the objective of
improving their pharmacological activities. Finally, 1,2,3-triazole cores may form the basis of small-molecule pharmaceutical leads.
Acknowledgements
V.S.P. is thankful to all her students and colleagues for their contributions
reviewed in this article. She is also grateful to the Indian Council of Medical Research for financial assistance (58/24/2007-BMS)
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Received: May 4, 2011
Published online: August 29, 2011
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2696 – 2718