1,2,3-Triazole analogs of combretastatin A-4 as potential microtubule-binding agents

A series of cis-restricted 1,4- and 1,5-disubstituted 1,2,3-triazole analogs of combretastatin A-4 (1) have been prepared. Cytotoxicity and tubulin inhibition studies showed that 2-methoxy-5-((5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)aniline (5e) and 2-methoxy-5-(1-(3,4,5-trimethoxybenzyl)-1H-1,2,3-triazol-5-yl)aniline (6e) were two of the most active compounds. Molecular modeling studies revealed that the N-2 and N-3 atoms in the triazole rings in 5e and 6e did not form hydrogen bonds with the amino acids in the anticipated pharmacophore.     

Synthesis of 1H-1,2,3-triazole derivatives as new α-glucosidase inhibitors and their molecular docking studies

Inhibition of α-glucosidase is an effective strategy for controlling the post-prandial hyperglycemia in diabetic patients. For the identification of new inhibitors of this enzyme, a series of new (R)-1-(2-(4-bromo-2-methoxyphenoxy) propyl)-4-(4-(trifluoromethyl) phenyl)-1H-1,2,3-triazole derivatives were synthesized (8a–d and 10a–e). The structures were confirmed by NMR, mass spectrometry and, in case of compound 8a, by single crystal X-ray crystallography. The α-glucosidase inhibitory activities were investigated in vitro. Most derivatives exhibited significant inhibitory activity against α-glucosidase enzyme. Their structure-activity relationship and molecular docking studies were performed to elucidate the active pharmacophore against this enzyme. Compound 10b was the most active analogue with IC₅₀ value of 14.2 µM, while compound 6 was found to be the least active having 218.1 µM. A preliminary structure-activity relationship suggested that the presence of 1H-1,2,3-triazole ring in 1H-1,2,3-triazole derivatives is responsible for this activity and can be used as anti-diabetic drugs. The molecular docking studies of all active compounds were performed, in order to understand the mode of binding interaction and the energy of this class of compounds.     

Microwave assisted synthesis and in vitro cytotoxicities of substituted (Z)-2-amino-5-(1-benzyl-1H-indol-3-yl)methylene-1-methyl-1H-imidazol-4(5H)-ones against human tumor cell lines

The synthesis of several novel substituted (Z)-2-amino-5-(1-benzyl-1H-indol-3-yl)methylene-1-methyl-1H-imidazol-4(5H)-ones structurally related to aplysinopsin have been carried out under microwave irradiation and conventional heating methods. The analogs 3a, 3b, 3d–3g, 3k and 3l were evaluated for their in vitro cytotoxic activity against an NCI 60 human tumor cell line panel. Compound 3f exhibited good growth inhibitory properties against all but four of the human cancer cell lines examined, and afforded LC₅₀ values <10 μM for 30% of the cell lines in the panel. Compound 3e was an effective inhibitor of leukemia, CNS, melanoma, and breast cancer cell growth, but generally less effective as a cytotoxic agent. Thus, the aplysinopsin analog 3f was regarded as a useful lead compound for further structural optimization.     

Isatin 1,2,3-triazoles as potent inhibitors against caspase-3

Sixteen disubstituted 1,2,3-triazoles were prepared using the Huisgen cycloaddition reaction and evaluated as inhibitors against caspase-3. The two most potent inhibitors were found to be (S)-1-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (7f) and (S)-1-((1-benzyl-1H-1,2,3-triazol-5-yl)methyl)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (8g) with IC₅₀-values of 17 and 9 nM, respectively. Lineweaver-Burk plots revealed that these two triazoles show competitive inhibitory mechanism against caspase-3.     

One-pot synthesis of 5-phenylimino, 5-thieno or 5-oxo-1,2,3-dithiazoles and evaluation of their antimicrobial and antitumor activity

We here report the synthesis and biological evaluation of rare 4-substituted-5-phenylimino, 5-thieno- and 5-oxo-1,2,3-dithiazoles. Dithiazoles were selectively obtained in moderate to high yields (25–73%) via a one-pot reaction from various ethanoneoximes with sulfur monochloride, pyridine in acetonitrile followed by treatment by corresponding nucleophiles (aniline, thioacetamide and formic acid). All the synthesized compounds were screened for their antibacterial (against bacteria Escherichia coli, Salmonella enterica serovar Typhimurium, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis, Bacillus cereus and Listeria inocua), antifungal (against pathogenic strains Candida albicans, Candida glabrata, Candida tropicalis and Issatchenkia orientalis) and antitumor (on human cell lines MCF-7 and MDA-MB-231) activity. 4-(2-Pyridinyl)-5H-1,2,3-dithiazole-5-thione and 4-ethylcarboxyl-5H-1,2,3-dithiazole-5-thione (5d, 5h) that are active against Gram-positive bacteria are significantly active against fungi. 4-(2-Benzofuranyl)-5-phenylimino-5H-1,2,3-dithiazole (4e) exerts antiproliferative activity.     

Synthesis,antiplatelet and in silico evaluations of novel N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides

This paper describes the synthesis, antiplatelet and theoretical evaluations of 10 N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides (2a–j). These compounds were synthesized, characterized and screened for their in vitro antiplatelet profile against human platelet aggregation using arachidonic acid, adrenaline and ADP as agonists. Among NAH derivatives 2a–j, the compounds 2a, 2c, 2e, 2g and 2h were the most promising molecules with significant antiplatelet activity.     

Synthesis,antimycobacterial activity and docking study of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives and related hydrazide-hydrazones

A new convenient method for preparation of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b–g and coumarin containing hydrazide-hydrazone analogues 4a–e was presented. The antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and cytotoxicity against the human embryonic kidney cell line HEK-293 were tested in vitro. All compounds demonstrated significant minimum inhibitory concentrations (MIC) ranging 0.28–1.69 μM, which were comparable to those of isoniazid. The cytotoxicity (IC₅₀ > 200 µM) to the “normal cell” model HEK-293T exhibited by 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b–e, was noticeably milder compared to that of their hydrazone analogues 4a–e (IC₅₀ 33–403 µM). Molecular docking studies on compounds 4a–e and 5b–g were also carried out to investigate their binding to the 2-trans-enoyl-ACP reductase (InhA) enzyme involved in M. tuberculosis cell wall biogenesis. The binding model suggested one or more hydrogen bonding and/or arene-H or arene-arene interactions between hydrazones or pyrazole-fused coumarin derivatives and InhA enzyme for all synthesized compounds.     

New bithiazolyl hydrazones: Novel synthesis,characterization and antitubercular evaluation

New bithiazolyl hydrazones (6a–l) have been first time synthesized by carrying novel one pot cyclocondensation of 5-acyl thiazoles (1a–b), thiosemicarbazide (2) and substituted phenacyl chlorides (4a–f) in freshly prepared ionic liquid, diisopropyl ethyl ammonium acetate (DIPEAc) at room temperature. The newly synthesized compounds have been evaluated for their antitubercular activity and the compounds 3b, 6a, 6b, 6d, 6e, 6f, 6g, and 6l have displayed noticeable antitubercular activity compared to Rifampicin with tolerable cytotoxicity. All these compounds were also screened for their antibacterial activity and found that, compounds 6j and 6k have exhibited a very good antibacterial activity. Molecular docking study has shown better harmony with the evaluation trend shown by these compounds under in vitro antitubercular screening.     

Synthesis,cytotoxicity, antimicrobial and anti-biofilm activities of novel pyrazolo[3,4-b]pyridine and pyrimidine functionalized 1,2,3-triazole derivatives

A series of novel pyrazolo[3,4-b]pyridine and pyrimidine functionalized 1,2,3-triazole derivatives 8a–g and 9a–g were prepared starting from 6-trifluoromethylpyridine-2(1H)one 2 via selective O-alkylation, followed by cyclisation using hydrazine hydrate to obtain 6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine 4. Compound 4 was diazotized followed by reaction with sodium azide, resulted in 3-azido-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine 5. Compound 5 was further cyclized with N-/O-propargylated pyrimidine derivatives under Sharpless conditions and obtained compounds 6 and 7, respectively. Each set of compounds 6 and 7 were alkylated with different alkyl halides and obtained respective products 8 and 9. All the products were screened for cytotoxicity against four human cancer cell lines such as A549-Lung (CCL-185), MCF7-Breast (HTB-22), DU145-Prostate (HTB-81) and HeLa-Cervical (CCL-2), compounds 9d, 9e and 9f which showed promising activity have been identified. The products were also screened for antimicrobial, anti bio-film and MBC activities. Promising compounds in each case have been identified.     

Synthesis,pharmacological screening and in silico studies of new class of Diclofenac analogues as a promising anti-inflammatory agents

A novel series of 5-[2-(2,6-dichlorophenylamino)benzyl]-3-(substituted)-1,3,4-oxadiazol-2(3H)-thione (4a–k) derivatives have been synthesized by the Mannich reaction of 5-[2-(2,6-dichlorophenylamino)benzyl]-1,3,4-oxadiazol-2(3H)-thione (3) with an appropriately substituted primary/secondary amines, in the presence of formaldehyde and absolute ethanol. Structures of these novel compounds were characterized on the basis of physicochemical, spectral and elemental analysis. The title compounds (4a–k) were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 10 mg/kg b.w. Compound 4k exhibited the most promising and significant anti-inflammatory profile while compounds 4a, 4d, 4e, 4i, and 4j showed moderate to good inhibitory activity at 2nd and 4th h, respectively. These compounds were also found to have considerable analgesic activity (acetic acid induced writhing model) and antipyretic activity (yeast induced pyrexia model). In addition, the tested compounds were also found to possess less degree of ulcerogenic potential as compared to the standard NSAIDs. Compounds that displayed promising anti-inflammatory profile were further evaluated for their inhibitory activity against cyclooxygenase enzyme (COX-1/COX-2), by colorimetric COX (ovine) inhibitor screening assay method. The results revealed that the compounds 4a, 4e, 4g and 4k exhibited effective inhibition against COX-2. In an attempt to understand the ligand–protein interactions in terms of the binding affinity, docking studies were performed using Molegro Virtual Docker (MVD-2013, 6.0) for those compounds, which showed good anti-inflammatory activity. It was observed that the binding affinities calculated were in agreement with the IC₅₀ values.     

Design,synthesis, 3D pharmacophore,QSAR, and docking studies of carboxylic acid derivatives as Histone Deacetylase inhibitors and cytotoxic agents

In this study, five series of (E)-6-(4-substituted phenyl)-4-oxohex-5-enoic acids IIb–f (E), (E)-3-(4-(substituted)-phenyl)acrylic acids IIIa–g (E), 4-(4-(substituted)phenylamino)-4-oxobutanoic acids VIa,b,e, 5-(4-(substituted)phenylamino)-5-oxopentanoic acids VIIa,f and 2-[(4-(substituted)phenyl) carbamoyl]benzoic acids VIIIa,e were designed and synthesized. Selected compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumor cell lines. Compound IIf (E) displayed significant inhibitory activity against NCI Non-Small Cell Lung A549/ATCC Cancer cell line (68% inhibition) and NCI-H460 Cancer cell line (66% inhibition). Moreover, the final compounds were evaluated in vitro for their cytotoxic activity on HepG2 Cancer cell line in which histone deacetylase (HDAC) is overexpressed. Compounds IIc (E), IIf (E), IIIb (E), and IIIg (E) exhibited the highest cytotoxic activity against HepG2 human cancer cell lines with IC₅₀ ranging from 2.27 to 10.71 μM. In addition, selected compounds were tested on histone deacetylase isoforms (HDAC1–11). Molecular docking simulation was also carried out for HDLP enzyme to investigate their HDAC binding affinity. In addition, generation of 3D-pharmacophore model and quantitative structure activity relationship (QSAR) models were combined to explore the structural requirements controlling the observed cytotoxic properties.     

Synthesis of novel 2-amino-4-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-6-aryl-4H-pyran-3-carbonitrile derivatives as antimicrobial and antioxidant agents

As a part of systematic investigation of synthesis and biological activities of indole analogues linked to various heterocyclic systems, we have synthesized new compounds viz., 2-amino-4-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-6-aryl-4H-pyran-3-carbonitriles (2a–i), 4,5-diamino-6-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-8-aryl-2-oxo-2,6-dihydrodipyrano [2,3-b:3,2-e]pyridine-3-carbonitriles (3a–i), 4-amino-5-(5′-substituted 2′-phenyl-1H-indol-3-yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-ones (4a–i), 4-amino-5-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-thiones (5a–i), 4-(5′-subtituted 2′-phenyl-1H-indol-3′-yl)-6-aryl-1,4-dihydropyrano[2,3-c]pyrazol-3-amines (6a–i) and 5-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-7-aryl-3H-pyrano[2,3-d]pyrimidin-4(5H)-ones (7a–i). Antibacterial activity results revealed that, compound 6a showed promising activity versus Escherichia coli, Staphylococcus aureus and Klebsiella pneumoniae. Compound 6d exhibited good activity against S. aureus, K. pneumoniae and Pseudomonas aeruginosa. Antifungal activity results indicated that, compound 4d exhibited maximum zone of inhibition against Aspergillus oryzae and Aspergillus flavus. In case of antioxidant activity, compound 4a showed promising radical scavenging activity, ferric ions (Fe³⁺) reducing antioxidant power (FRAP) and metal chelating activity.     

Synthesis of new 1-(4-methane(amino)sulfonylphenyl)-5-(4-substituted-aminomethylphenyl)-3-trifluoromethyl-1H-pyrazoles: A search for novel nitric oxide donor anti-inflammatory agents

A group of 1-(4-methane(amino)sulfonylphenyl)-5-(4-substituted-aminomethylphenyl)-3-trifluoromethyl-1H-pyrazoles (12a–f) was synthesized and evaluated as anti-inflammatory agents. While all the compounds (20 mg/kg) showed significant anti-inflammatory activity after 3 h of inflammation induction (69–89%) as compared to celecoxib (80%), 1-(4-methanesulfonylphenyl)-5-(4-methylaminomethylphenyl)-3-trifluoromethyl-1H-pyrazole (12a) was found to be the most effective one (89%). The synthesis of model hybrid nitric oxide donor N-diazen-1-ium-1,2-diolate derivatives of 1-(4-methanesulfonylphenyl)-5-(4-substituted-aminomethylphenyl)-3-trifluoromethyl-1H-pyrazoles (10a–f) requires further investigation since the reaction of N-(4-(1-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzyl)ethanamine (12b) or 1-(4-(1-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzyl)piperazine (12c) with nitric oxide furnished N-nitroso derivatives (13 and 14), respectively, rather than the desired N-diazen-1-ium-1,2-diolate derivatives (10b and 10c).     

Solvent free,catalyst free,microwave or grinding assisted synthesis of bis-cyclic imide derivatives and their evaluation for anticancer activity

Cyclic imides are well known to be very important antitumor agents such as mitonafide and amonafide etc. Based on this fact, we have synthesized two series of cyclic imide derivatives containing two cyclic imide moiety in their structures (bis-cyclic imides) and screened them for in vitro anticancer activity against five human cancer cell lines i.e. breast (T47D), lung (NCl H-522), colon (HCT-15), ovary (PA-1) and liver (Hep G2). One series of bis-cyclic imide derivatives (3a–h) have been synthesized by condensation of acid anhydrides (1a–b) with diamines (2a–d) and another series (9a–f, 10a–f, 11a–f and 12a–f) by condensation of various diamines (4a–f) with diacids (5–8) in good yields. Structures assigned to 3a–h, 9a–f, 10a–f, 11a–f and 12a–f were fully characterized by spectroscopic means and elemental analysis. On screening for in vitro anticancer activity, compounds 3a (breast T47D), 3d (breast T47D, liver Hep G2), 3e (breast T47D, liver Hep G2), 3h (colon HCT-15), 10f (liver Hep G2) and 11a (colon HCT-15, ovary PA-1) exhibited good anticancer activities with IC₅₀ values range from 12.41 ± 3.2 to 17.9 ± 2.5 μM.     

Thiazolyl-pyrazole derivatives as potential antimycobacterial agents

Mycobacterium tuberculosis (Mtb) is an obligate aerobe that is capable of long-term persistence under conditions of low oxygen tension. A series of thiazolyl-pyrazole derivatives (6a–f, 7a–f, 8c, 8e) were screened for antimycobacterial activity against dormant M. tuberculosis H37Ra (D-MTB) and M. bovis BCG (D-BCG). Nine thiazolyl-pyrazole analogs, 6c, 6e, 7a, 7b, 7c, 7e, 7f, 8c and 8e exhibited promissing minimum inhibitory concentration (MIC) values (0.20–28.25?µg/mL) against D-MTB and D-BCG strains of Mtb. Importantly, six compounds (7a, 7b, 7e, 7f, 8c and 8e) exhibited excellent antimycobacterial activity and low cytotoxicity at the maximum evaluated concentration of >250?µg/mL. Finally, the promising antimycobacterial activity and lower cytotoxicity profile suggested that, these compounds could be further subjected for optimization and development as a lead, which could have the potential to treat tuberculosis.     

Facile synthesis of new imidazo[1,2-a]pyridines carrying 1,2,3-triazoles via click chemistry and their antiepileptic studies

The present article reports the synthesis and anticonvulsant studies of new 2-arylimidazo[1,2-a]pyridines carrying suitably substituted 1,2,3-triazoles as well as their intermediates. The structures of newly synthesized compounds were confirmed by various spectroscopic techniques. The anticonvulsant study was carried out by MES and scPTZ screening methods, while their toxicity study was performed following Rotarod method. The active compounds showed enhanced seizure control in scPTZ method when compared with that of MES method. Compounds 3f, 4c, 4f, 5k, 5p and 5w carrying active pharmacophores exhibited complete protection against seizure and their results were comparable with standard drug diazepam. Majority of new compounds were found to be non-toxic, while few of them showed toxicity at 100 mg/kg. The c log P values of target compounds are in the range of 3.5–5.3, which confirm their lipophilic nature.     

Indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones: Synthesis,characterization and evaluation of anticancer and antimicrobial activities

A series of novel 10-((1H-indol-3-yl)methylene)-7-aryl-7,10-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-ones (8a–t) have been synthesized in good yields by the reaction of benzo[h]quinazoline-2(1H)-thiones (4a–f) with 2-chloro-N-phenylacetamide (5) followed by Knoevenagel condensation with various indole-3-carbaldehydes (7a–d) under conventional method. All the synthesized compounds were characterized by spectral studies and screened for their in vitro anticancer and antimicrobial activities. Compound 8c has exhibited excellent activity against MCF-7 (breast cancer cell line) than the standard drug Doxorubicin. Compound 8d against both the cancer cell lines, 8q against MCF-7 and 8c, 8h against HepG2 have also shown good activity. Remaining compounds have shown moderate activity against both the cell lines. Antimicrobial activity revealed that, the compound 8q and 8t against Staphylococcus aureus and 8i, 8k, 8l, 8q & 8t against Klebsiella pneumoniae have shown equipotent activity on comparing with the standard drug Streptomycin. Remaining compounds have shown significant antibacterial and comparable antifungal activities against all the tested microorganisms.     

Synthesis and antimicrobial activity of novel fluorine containing 4-(substituted-2-hydroxybenzoyl)-1H-pyrazoles and pyrazolyl benzo[d]oxazoles

A series of fluorine containing 4-(substituted-2-hydroxybenzoyl) pyrazoles and pyrazolyl benzo[d]oxazoles were synthesized and evaluated for their antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Bacillus subtilis and antifungal activity against Candida albicans. The antibacterial activities were expressed as the minimum inhibitory concentration (MIC₅₀) in μg/ml. The compounds 1-(3,4-difluorophenyl)-4-(5-fluoro-2-hydroxybenzoyl)-1H-pyrazole (4b), oxime derivatives such as 1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)(2-hydroxy-4-methylphenyl)methanone oxime (5b) and (5-chloro-2-hydroxyphenyl)(1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)methanone oxime (5e) exhibited promising activities against tested bacterial strains. Except compound 1-(3,4-difluorophenyl)-4-(2-hydroxybenzoyl)-1H-pyrazole (4d), none of the other compounds showed promising antifungal activity.     

Synthesis,antitumor activity evaluation and mechanistic study of novel hederacolchiside A1 derivatives bearing an aryl triazole moiety

In an attempt to arrive at a more potent antitumor agent than the parent natural saponin hederacolchiside A₁, 23 hederacolchiside A₁ derivatives (4a-4w) were synthesized via Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition and screened in vitro for cytotoxicity against six human cancer cell lines. The structure-activity relationship of these compounds was elucidated, and the biological screening results showed that most of the compounds exhibited moderate to high levels of antitumor activities against the tested cell lines and some of them displayed more potent inhibitory activities compared with hederacolchiside A₁. Compound 4f showed a 2- to 7-fold more potent activity than hederacolchiside A₁. The mechanistic study of 4f revealed that this compound can induce cell apoptosis in HepG2 cells via mitochondrial-mediated intrinsic pathways.     

4-Substituted 4-(1H-1,2,3-triazol-1-yl)piperidine: Novel C7 moieties of fluoroquinolones as antibacterial agents

A series of 4-substituted 4-(1H-1,2,3-triazol-1-yl)piperidine building blocks was synthesized and introduced to the C7 position of the quinolone core, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, to afford the corresponding fluoroquinolones in 40–83% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. Among them, the quinolone 1-cyclopropyl-6-fluoro-7-(4-(4-formyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (34.15) exhibited comparable antibacterial activity against quinolone-susceptible and multidrug-resistant strains, especially to Staphylococcus aureus and Staphylococcus epidermidis, in comparison with ciprofloxacin and vancomycin.