Synthesis and evaluation of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives as xanthine oxidase inhibitors

This study mainly focused on the modification of the X² position in febuxostat analogs. A series of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives (1a-s) with an N atom occupying the X² position was designed and synthesized. Evaluation of their inhibitory potency in vitro on xanthine oxidase indicated that these compounds exhibited micromolar level potencies, with IC₅₀ values ranging from 0.21 µM to 26.13 μM. Among them, compound 1s (IC₅₀ = 0.21 μM) showed the most promising inhibitory effects and was 36-fold more potent than allopurinol, but was still 13-fold less potent than the lead compound Y-700, which meant that a polar atom fused at the X² position could be unfavorable for potency. The Lineweaver-Burk plot revealed that compound 1s acted as a mixed-type xanthine oxidase inhibitor. Analysis of the structure-activity relationships demonstrated that a more lipophilic ether tail (e.g., meta-methoxybenzoxy) at the 4′-position could benefit the inhibitory potency. Molecular modeling provided a reasonable explanation for the structure–activity relationships observed in this study.     

Synthesis and biological evaluation of novel indole-pyrazoline hybrid derivatives as potential topoisomerase 1 inhibitors

A series of novel indole-pyrazoline hybrid derivatives were designed, synthesized, and evaluated for topoisomerase 1 (Top1) inhibitory activity. Top1-mediated relaxation assays showed that our synthesized compounds had variable Top1 inhibitory activity. Among these compounds, 3-(5-(naphthalen-1-yl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-1-(phenylsulfonyl)-1H-indole (6n) was found to be a strong Top1 inhibitor with better inhibitory activity than CPT and hit compounds. Our further experiments rationalized the mode of action for this new type of inhibitors, which showed no significant binding to supercoiled DNA.     

Synthesis and biological evaluation of naphthoquinone-coumarin conjugates as topoisomerase II inhibitors

Based on previous Topoisomerase II docking studies of naphthoquinone derivatives, a series of naphthoquinone-coumarin conjugates was synthesized through a multicomponent reaction from aromatic aldehydes, 4-hydroxycoumarin and 2-hydroxynaphthoquinone. The hybrid structures were evaluated against the α isoform of human topoisomerase II (hTopoIIα), Escherichia coli DNA Gyrase and E. coli Topoisomerase I. All tested compounds inhibited the hTopoIIα-mediated relaxation of negatively supercoiled circular DNA in the low micromolar range. This inhibition was specific since neither DNA Gyrase nor Topoisomerase I were affected. Cleavage assays pointed out that naphthoquinone-coumarins act by catalytically inhibiting hTopoIIα. ATPase assays and molecular docking studies further pointed out that the mode of action is related to the hTopoIIα ATP-binding site.     

Synthesis and biological evaluation of 4-(1,2,3-triazol-1-yl)coumarin derivatives as potential antitumor agents

In this research, a series of 4-(1,2,3-triazol-1-yl)coumarin conjugates were synthesized and their anticancer activities were evaluated in vitro against three human cancer cell lines, including human breast carcinoma MCF-7 cell, colon carcinoma SW480 cell and lung carcinoma A549 cell. To increase the biological potency, structural optimization campaign was conducted focusing on the C-4 position of 1,2,3-triazole and the C-6, C-7 positions of coumarin. In addition, to further evaluate the role of 1,2,3-triazole and coumarin for antiproliferative activity, 9 compounds possessing 4-(piperazin-1-yl)coumarin framework and 3 derivatives baring quinoline core were also synthesized. By MTT assay in vitro, most of the compounds display attractive antitumor activities, especially 23. Further flow cytometry assays demonstrate that compound 23 exerts the antiproliferative role through arresting G₂/M cell-cycle and inducing apoptosis.     

Synthesis and biological evaluation of novel carbazole-rhodanine conjugates as topoisomerase II inhibitors

In this study, a series of carbazole-rhodanine conjugates was synthesized and evaluated for their Topoisomerase II inhibition potency as well as cytotoxicity against a panel of four human cancer cell lines. Among these thirteen compounds, 3a, 3b, 3g, and 3h possessed Topoisomerase II inhibition potency at 20?μM. Mechanism study revealed that these compounds may function as Topo II catalytic inhibitors. It was found that the electron-withdrawing groups on the phenyl ring of compounds played an important role on enhancing both enzyme inhibition and cytotoxicity.     

Synthesis and cyclooxygenase inhibition of various (aryl-1,2,3-triazole-1-yl)-methanesulfonylphenyl derivatives

A series of 1,4- and 1,5-diaryl substituted 1,2,3-triazoles was synthesized by either Cu(I)-catalyzed or Ru(II)-catalyzed 1,3-dipolar cycloaddition reactions between 1-azido-4-methane-sulfonylbenzene 9 and a panel of various para-substituted phenyl acetylenes (4-H, 4-Me, 4-OMe, 4-NMe₂, 4-Cl, 4-F). All compounds were used in in vitro cyclooxygenase (COX) assays to determine the combined electronic and steric effects upon COX-1 and COX-2 inhibitory potency and selectivity. Structure-activity relationship studies showed that compounds having a vicinal diaryl substitution pattern showed more potent COX-2 inhibition (IC₅₀ = 0.03–0.36 μM) compared to their corresponding 1,3-diaryl-substituted counterparts (IC₅₀ = 0.15 to >10.0 μM). In both series, compounds possessing an electron-withdrawing group (Cl and F) at the para-position of one of the aryl rings displayed higher COX-2 inhibition potency and selectivity as determined for compounds containing electron-donating groups (Me, OMe, NMe₂). The obtained data show, that the central carbocyclic or heterocyclic ring system as found in many COX-2 inhibitors can be replaced by a central 1,2,3-triazole unit without losing COX-2 inhibition potency and selectivity. The high COX-2 inhibition potency of some 1,2,3-triazoles having a vicinal diaryl substitution pattern along with their ease in synthesis through versatile Ru(II)-catalyzed click chemistry make this class of compounds interesting candidates for further design and synthesis of highly selective and potent COX-2 inhibitors.     

Synthesis and biological evaluation of (4H-1,2,4-triazol-4-yl)isoquinoline derivatives as selective glycine transporter 1 inhibitors

To identify novel glycine transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure-activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.     

Synthesis and biological evaluation of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides as antimitotic agents

A library of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides (7a–al) have been designed, synthesized and screened for their anti-proliferative activity against some selected human cancer cell lines namely DU-145, A-549, MCF-7 and HeLa. Most of them have shown promising cytotoxicity against lung cancer cell line (A549), amongst them 7f was found to be the most potent anti-proliferative congener. Furthermore, 7f exhibited comparable tubulin polymerization inhibition (IC₅₀ value 2.04 µM) to the standard E7010 (IC₅₀ value 2.15 µM). Moreover, flow cytometric analysis revealed that this compound induced apoptosis via cell cycle arrest at G₂/M phase in A549 cells. Induction of apoptosis was further observed by examining the mitochondrial membrane potential and was also confirmed by Hoechst staining as well as Annexin V-FITC assays. Furthermore, molecular docking studies indicated that compound 7f binds to the colchicine binding site of the β-tubulin. Thus, 7f exhibits anti-proliferative properties by inhibiting the tubulin polymerization through the binding at the colchicine active site and by induction of apoptosis.     

Design,synthesis and biological evaluation of novel perimidine o-quinone derivatives as non-intercalative topoisomerase II catalytic inhibitors

For the development of novel anticancer agents, we designed and synthesized a total of 37 perimidine o-quinone derivatives containing the o-quinone group at the A or B ring and different substituents (alkyl groups, aryl groups or heterocycles) at the C ring of the compounds. The structure-activity relationships (SARs) were established based on the cytotoxicity data of compounds from the HL-60, Huh7, Hct116, and Hela cell lines. The cytotoxicity results showed that most compounds exhibited potent cytotoxicity. In particular, compound b-12 showed the best anti-proliferative activity (IC₅₀ ≤ 1 μM) against four cancer cell lines and strong potency against the HL-60/MX2 (0.47 μM) cell line, which is resistant to Topo II poisons. Further studies showed that b-12 exhibited potent Topo IIα inhibitory activity (IC₅₀ = 7.54 μM) compared with Topo I, which acted as a class of non-intercalative Topo IIα catalytic inhibitor by inhibiting the ATP binding site of Topo II. Cell apoptosis and cell cycle assays confirmed that b-12 could induce the apoptosis of Huh7 cells in a dose-dependent manner.     

Discovery and biological evaluation of some (1H-1,2,3-triazol-4-yl)methoxybenzaldehyde derivatives containing an anthraquinone moiety as potent xanthine oxidase inhibitors

A series of (1H-1,2,3-triazol-4-yl)methoxybenzaldehyde derivatives containing an anthraquinone moiety were synthesized and identified as novel xanthine oxidase inhibitors. Among them, the most promising compounds 1h and 1k were obtained with IC₅₀ values of 0.6 μM and 0.8 μM, respectively, which were more than 10-fold potent compared with allopurinol. The Lineweaver-Burk plot revealed that compound 1h acted as a mixed-type xanthine oxidase inhibitor. SAR analysis showed that the benzaldehyde moiety played a more important role than the anthraquinone moiety for inhibition potency. The basis of significant inhibition of xanthine oxidase by 1h was rationalized by molecular modeling studies.     

Synthesis and biological evaluation of 2-phenol-4-chlorophenyl-6-aryl pyridines as topoisomerase II inhibitors and cytotoxic agents

A new series of 2-phenol-4-chlorophenyl-6-aryl pyridines were designed, synthesized, and evaluated for topoisomerase (topo) I and II inhibitory activities as well as cytotoxic activity against four different human cancer cell lines such as HCT15, T47D, DU145, and Hela. Most of the tested compounds exhibited stronger topo II inhibitory activity at 100 μM as compared to etoposide. All the compounds, except 39, did not show topo I inhibitory activity. Interestingly, compounds that showed better topo II inhibition than etoposide have ortho- or para-chlorophenyl at 4-position of central pyridine, and none of the compounds possess meta-chlorophenyl. SAR study revealed the importance of ortho- or para-chlorophenyl at 4-position of the central pyridine for selective topo II inhibitory activity. Similarly, all compounds possessing meta- or para-hydroxyphenyl moieties showed moderate to significant cytotoxic effects. Particularly, compounds 27–37, and 39 which showed excellent cytotoxicity (IC₅₀ = 0.68–1.25 μM) against T47D breast cancer cells suggest the importance of meta- or para-hydroxyphenyl moiety at 2-position of the central pyridine for the design of anticancer agents with related scaffolds.     

Synthesis and biological evaluation of phenyl-1H-1,2,3-triazole derivatives as anti-inflammatory agents

Rapid and efficient synthesis of a phenyl-1H-1,2,3-triazole library enabled cost-effective biological testing of a range of novel non-steroidal anti-inflammatory drugs with potential for improved drug efficacy and toxicity profiles. Anti-inflammatory activities of the phenyl-1H-1,2,3-triazole analogs synthesized in this report were assessed using the xylene-induced ear edema model in mice. At least four analogs, 2a, 2b, 2c, and 4a, showed more potent effects than the reference anti-inflammatory drug diclofenac at the same dose of 25 mg/kg. To explore relationships between the structural properties of phenyl-1H-1,2,3-triazole analogs and their anti-inflammatory activities in xylene-induced ear edema, comparative molecular field analysis was performed, and pharmacophores showing good anti-inflammatory activities were identified based on an analysis of contour maps obtained from comparative molecular field analysis. The anti-inflammatory effect on the molecular level was tested by the expression of tumor necrosis factor-alpha induced COX-2 using Western blots. Because the addition of the analog 2c caused the expression change of TNF-α induced COX-2, the molecular binding mode between 2c and COX-2 was elucidated using in silico docking.     

Discovery andw biological evaluation of novel 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety as c-Met kinase inhibitors

A series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and five typical cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG). Most compounds showed moderate to excellent antiproliferative activity. In this study, a promising compound 34, with a c-Met IC₅₀ value of 1.04 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor. The SAR analyses indicated that compounds with halogen group, especially fluoro group, at 4-position on the phenyl ring (moiety B) have potent antitumor activity, and methylation on the 5-atom linker played an important role in the c-Met enzymatic activity.     

Synthesis and biological evaluation of substituted imidazoquinoline derivatives as mPGES-1 inhibitors

We have previously reported 7-bromo-2-(2-chrolophenyl)-imidazoquinolin-4(5H)-one (1) as a novel potent mPGES-1 inhibitor. To clarify the essential functional groups of 1 for inhibition of mPGES-1, we investigated this compound structure–activity relationship following substitution at the C(4)-position and N-alkylation at the N(1)-, the N(3)-, and the N(5)-positions of 1. To prepare the target compounds, we established a good methodology for selective N-alkylation of the imidazoquinolin-4-one, that is, selective alkylation of 1 at the N(3)- and N(5)-positions was achieved by use of an appropriate base and introduction of a protecting group at the nitrogen atom in the imidazole part, respectively. Replacement of the C(4)-oxo group with nitrogen- or sulfur- linked substituents gave decreased inhibitory activity for mPGES-1, and introduction of alkyl groups on the nitrogen atom at the N(1)-, the N(3)-, and the N(5)-positions resulted in even larger loss of inhibitory activity. These results revealed that the C(4)-oxo group, and the hydrogen atoms at the N(5)-position and the imidazole part were the best substituents.     

Synthesis and biological evaluation of N-mercaptoacylcysteine derivatives as leukotriene A4 hydrolase inhibitors

We studied synthetic modifications of N-mercaptoacylamino acid derivatives to develop a new class of leukotriene A₄ (LTA₄) hydrolase inhibitors. S-(4-Dimethylamino)benzyl-l-cysteine derivative 2a (SA6541) showed inhibitory activity against LTA₄ hydrolase (IC₅₀, 270 nM) and selectivity over other metallopeptidases except angiotensin-converting enzyme (ACE, IC₅₀, 520 nM). Modification at the para-substituent of the phenyl ring of compound 2a improved LTA₄ hydrolase inhibitory activity as well as selectivity over ACE. Finally, we obtained S-(4-cyclohexyl)benzy-l-cysteine derivatives 11l and 16i as potent and selective LTA₄ hydrolase inhibitors.     

Synthesis, characterization and biological activity of triorganotin 2-phenyl-1,2,3-triazole-4-carboxylates

The triorganotin 2-phenyl-1,2,3-triazole-4-carboxylates, 2-PhC2N3CO2SnR3 (R=C6H5, 1; c-C6H11, 2; C6H5C(CH3)2CH2, 3), have been prepared and characterized by means of elemental analysis, IR and NMR (1H, 13C and 119Sn) spectroscopy. The crystal structures of 1 and 3 have been determined. Compound 1 is polymeric in nature with a trigonal bipyramidal configuration, and compound 3 shows a tetrahedral geometry. Bioassay results have shown that these compounds have good antibacterial and antitumor activity. The activity against three human tumor cell lines (HeLa, CoLo205 and MCF-7) decreased in the order 1>2>3.     

Synthesis and biological evaluation of novel 1,2,3-triazole derivatives as anti-tubercular agents

A library of seventeen novel 1,2,3-triazole derivatives were efficiently synthesized in excellent yields by the popular ‘click chemistry’ approach and evaluated in vitro for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain). Among the series, six compounds exhibited significant activity with minimum inhibitory concentration (MIC) values ranging from 3.12 to 0.78 μg/mL and along with no significant cytotoxicity against MBMDMQs (mouse bone marrow derived macrophages). Molecular docking of the target compounds into the active site of DprE1 (Decaprenylphosphoryl-β-d-ribose-2′-epimerase) enzyme revealed noteworthy information on the plausible binding interactions.     

Synthesis and biological evaluation of 4beta-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxins as potential anticancer agents

A series of novel 4beta-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxin derivatives were synthesized by employing Cu(I)-catalyzed click chemistry and evaluated for their anticancer activity against a panel of seven human cancer cell lines (HT-29, HCT-15, 502713, HOP-62, A-549, MCF-7, and SF-295). The compounds 9b, 9c, 9e, 9f, and 9h showed significant cytotoxic activities especially against HT-29, HCT-15, 502713 cell lines.     

1H-1,2,3-Triazol-1-yl thiodigalactoside derivatives as high affinity galectin-3 inhibitors

Galactose C3-triazole derivatives were synthesized by Cu(I)-catalyzed cycloaddition between acetylenes and galactose C3-azido derivatives. Evaluation against galectin-3, 7, 8N (N-terminal) and 9N (N-terminal) revealed 1,4-disubstituted triazoles to be high-affinity inhibitors of galectin-3 with selectivity over galectin-7, 8N, and 9N. Conformational analysis of 1,4-di- and 1,4,5-tri-substituted galactose C3-triazoles suggested that a triazole C5-substituent interfered sterically with the galectin proteins, which explained their poor affinities compared to the corresponding 1,4-disubstituted triazoles. Introduction of two 1,4-disubstituted triazole moieties onto thiodigalactoside resulted in affinities down to 29 nM for galectin-3.     

Synthesis and biological evaluation of Isosteviol derivatives as FXa inhibitors

Firstly, a series of Isosteviol derivatives were synthesized and evaluated for FXa inhibitory activity. Among these compounds, the inhibitory activity of compounds 22, 35 and 38 on FXa was better than that of Isosteviol. Secondly, surface plasmon resonance (SPR) assays were performed for selected compounds. Compounds 22, 35, 38 have similar kinetic signatures, and affinity values were at μM level. Thirdly, compounds 22 and 35 displayed moderate-to-high anticoagulation activity and showed similar sensitivity to PT and aPTT. These findings will provide new insight into the exploration of FXa inhibition.