Synthesis and pharmacological evaluation of novel 4-isopropylthiazole-4-phenyl-1,2,4-triazole derivatives as potential antimicrobial and antitubercular agents

A series of novel 4-isopropylthiazol-4-phenyl-1,2,4-triazol derivatives, N′-(substituted benzylidene)-2-(5-(4-isopropylthiazol-2-yl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)acetohydrazides 4a–e, 4-isopropylthiazol-2-yl-4′-phenyl-4′H-1′, 2′,4′-triazol-3′-ylthio (substituted methyl benzylidene) acetohydrazides 5a–f, 3-(4-isopropylthiazol-2-yl)-4-phenyl-5-(5-substituted-1,3,4-oxadiazol-2-ylthio)-4H-1,2,4-triazole derivatives 6a–f and N-acetyl-5′-(4-isopropylthiazol-2-yl)-4′-phenyl-4′H-1,2,4-triazol-3′-ylthio) acetohydrazide 7 were synthesized and characterized by spectroscopy, elemental, and mass spectral analysis. These compounds were evaluated for their preliminary in vitro antibacterial, antifungal, and antitubercular activity against Mycobacterium tuberculosis (M. tuberculosis) H37Rv strain by broth dilution assay method. All the compounds exhibited moderate to significant antibacterial and antifungal activities. Results of the antitubercular screening against Mycobacterium tuberculosis H37Rv showed that compounds 4c and 6c exhibited good antitubercular activity when compared with first line drug isoniazid.     

Antimicrobial activity of Schiff bases of coumarin-incorporated 1,3,4-oxadiazole derivatives: an in vitro evaluation

A series of 3-{5-[(E)-(substituted benzylidene) amino]-1,3,4-oxadiazol-2-yl}-2H-chromen-2-ones (4a–r) were synthesized by the reaction of 3-(5-amino]-1,3,4-oxadiazol-2-yl}-2H-chromen-2-one with different substituted benzaldehydes to form Schiff bases of coumarin-incorporated 1,3,4-oxadiazole derivatives. The structures of the compounds were confirmed on the basis of their elemental analysis and spectral data. The compounds were screened against bacterial strains Staphylococcus aureus NCTC (10418), Escherichia coli NCTC (6571), and fungal strain Candida albicans ATCC (10231). Ciprofloxacin and Ketoconazole were used as standards. The test compounds and standards were evaluated at 100 μg/ml concentration. DMF (N,N-dimethylformamide) was used as solvent and control. Most of the synthesized compounds possess significant antimicrobial activity. Compound (4m) without any substitution of the phenyl ring which is attached to 1,3,4-oxadiazole moiety showed highly significant in vitro growth inhibition against S. aureus and E. coli, while as compound (4g) with para N(CH₃)₂ showed highly significant in vitro growth inhibition against C. albicans.     

Synthesis of novel 3-(5-sulfanyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one condensed s-triazinyl piperazines and piperidines as antimicrobial agents

Synthesis and antimicrobial activity of a new series of 3-(5-sulfanyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-ones based on various substituted piperazines and piperidines incorporating a 1,3,5-triazine moiety are reported in this article. 3-{5-[(4,6-dichloro-1,3,5-triazin-2-yl)sulfanyl]-1,3,4-oxadiazol-2-yl}-2H-chromen-2-one 3 was obtained by the reaction of 2,4,6-trichloro-1,3,5-triazine 1 with 3-(5-sulfanyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one 2 which was obtained by following the method reported in the literature. Intermediate 3 was then condensed with 8-hydroxyquinoline 4 to form 3-(5-{[4-chloro-6-(quinolin-4-yloxy)-1,3,5-triazin-2-yl]sulfanyl}-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one 5. This was further treated with various substituted piperazines and piperidines to obtain the title compounds 7a–u, which were then subjected to determine their in vitro biological efficacy against bacterial and fungal strains as two Gram-positive bacteria (S. aureus, B. cereus), six Gram-negative bacteria (E. coli, P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris, and S. flexneria) and two fungal species (A. niger, and C. albicans) with an intent to develop novel class of antimicrobial agents. The results indicate that some of the novel s-triazines have noteworthy activity in MIC (μg/ml) and zone of inhibition (mm) indicating potential leads for further drug discovery study. All the final compounds were structurally elucidated on the basis of IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR spectroscopy, and elemental analysis.     

Synthesis of new oxadiazole derivatives as anti-inflammatory, analgesic, and antimicrobial agents

In search of pharmalogically active molecules in the class of oxadiazoles, the present article deals with the synthesis of 5-(5′-fluoro-2′-methoxybiphenyl-3-yl)-1,3,4-oxadiazol-2(3H)-one 2 from its hydrazide analog 1. The compound 2 was regioselectively N-alkylated with alkyl halides and produced the compounds 3a–f. Compound 3f was further functionalized with substituted benzenesulfonyl chlorides to give compounds 3g–j. The synthesized compounds were characterized by elemental and spectral analysis. Newly synthesized compounds were tested for their in vivo anti-inflammatory, analgesic, and in vitro antimicrobial activities. The compounds 3a–c were found to have promising anti-inflammatory and analgesic activities. Compounds 3b, 3f, and 3g showed significant antibacterial and antifungal activities.     

Antimicrobial and antiurease activities of newly synthesized morpholine derivatives containing an azole nucleus

2-[6-(Morpholin-4-yl)pyridin-3-ylamino]acetohydrazide (4) was obtained starting from 6-morpholin-4-ylpyridin-3-amine (2) via the formation of ester (3) and then converted to the corresponding Schiff bases (5, 6) with the reaction with aromatic aldehydes. The carbothioamide (9), obtained from the reaction of hydrazide with phenylisothiocyanate, was converted to the corresponding 1,2,4-triazole (11) and 1,3,4-thiadiazole (12) derivatives by the treatment with NaOH or H₂SO₄, respectively. The cyclocondenzation of 9 with 4-chlorophenacyl bromide or ethyl bromoacetate produced the corresponding 1,3-thiazole (10) or 1,3-thiazolidine derivatives (13), respectively. Antimicrobial and antiurease activities of newly synthesized compounds were investigated. Some of them were found to be active on M. smegmatis, and they displayed activity toward C. albicans and S. cerevisiae in high concentration. Compound 10 proved to be the most potent showing an enzyme inhibition activity with an IC₅₀ = 2.37 ± 0.19 μM.     

Substituted phenyl containing 1,3,4-oxadiazole-2-yl-but-2-enamides: synthesis and preliminary evaluation as promising anticonvulsants

A series of 3-(4-substitutedphenyl)-N-(5-(4-substitutedphenyl-1,3,4-oxadiazol-2-yl)but-2-enamide were synthesized using pharmacophoric elements for in vivo anticonvulsant activity yielding two potent candidates (4d and 4j) in the Phase I and Phase II screening employing maximal electroshock seizure and subcutaneous pentylenetetrazole test having minimal neurotoxicity. Their Phase II screen depicted an increment of nearly 2–10 times for MES and 7–67 folds for scPTZ in the therapeutic index and protective index—the two mainstays in the drug discovery.     

Design and synthesis of 3-(4-chlorophenyl)-2-(2-(4-substituted)-2-oxoethylthio)quinazolin-4(3H)-one as antihistamine agents

A series of novel 3-(4-chlorophenyl)-2-(2-(4-substituted)-2-oxoethylthio)quinazolin-4(3H)-one was synthesized by the reaction of 2-(3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetyl chloride with various amines. The starting material, (3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetyl chloride was synthesized from 4-chloroaniline by a multistep synthesis. All the title compounds were tested for their in vivo H₁-antihistaminic activity on conscious guinea pigs at the dose level of 10 mg/kg using chlorpheniramine maleate as the reference standard. The results of the biological activity indicate that the test compounds protected the animals from histamine-induced bronchospasm significantly. Compound 3-(4-chlorophenyl)-2-(2-(4-methylpiperazin-1-yl)-2-oxoethylthio)quinazolin-4(3H)-one (1) emerged as the most potent compound of the series (71.13 % protection) when compared to the reference standard chlorpheniramine maleate (70.09 % protection). Interestingly, compound A1 shows negligible sedation (12 %) compared to chlorpheniramine maleate (32 %). Therefore, compound A1 can serve as the lead molecule for further development.     

Design, synthesis, anti-inflammatory, analgesic screening, and molecular docking of some novel 2-pyridyl (3H)-quinazolin-4-one derivatives

A novel series of 6-bromo-2-(4-pyridyl)-quinazolin-4(3H)-ones were synthesized by reacting 5-bromo anthranilic acid with isonictinoly chloride in the presence of acetic anhydride, which were further reacted with p-amino acetophenone to obtain 3-(4-acetylphenyl)-6-bromo-2-(pyridin-4-yl)quinazolin-4(3H)-one (3). Compound 3 underwent further reactions with different aldehydes to afford chalcone derivatives 4–10, which in turn underwent various cyclization reactions to afford cyclized products 15–18. 2-aminothiazole derivatives 12 obtained by reaction of 3 with bromine then with thiourea. Compound 14 obtained by treatment of 11 with KSCN followed by cyclization. Some of the synthesized compounds 4, 5, 12, 14, 15 and 18 were screened for both analgesic and anti-inflammatory activities. All tested compounds showed good analgesic and anti-inflammatory activity in comparison to the reference standard indomethacin. Compounds 4 and 5 showed the highest anti-inflammatory activity, while compounds 14 and 15 showed the highest analgesic activity among all the tested compounds.     

Synthesis, hypolipidemic, and anti-inflammatory activities of arylphthalimides

Phthalimide and some N-substituted cyclic imides may be potent hypolipidemic agents, capable of reducing plasma cholesterol, and triglyceride levels. In this work, N-phenylphthalimide (5a), N-(2-nitrophenyl)phthalimide (5b), N-(3-nitrophenyl)phthalimide (5c), N-(4-nitrophenyl)phthalimide (5d), N-(4-bromophenyl)phthalimide (5e), N-(4-amidaphenyl)phthalimide (5f), N-(4-methylthiophenyl)phthalimide (5g), and N-(4-chlorophenyl)phthalimide (5h) were synthesized, and their effects on reducing lipid levels and as acute antiinflammatory agents in 3-month-old male Swiss mice were compared with phthalimide. To access their safety, the drugs were administered to determine the acute toxicity (LD₅₀ value). In addition, the acute anti-inflammatory activity was evaluated via carrageenan-induced edema; and the effective dose was determined for compounds that showed the best anti-inflammatory activity in comparison with ibuprofen. The compound (5g) proved to be a more active hypolipidemic compound than phthalimide, at a dose level of 20 mg kg^?1 day^?1. The derivative (5g) reduced the plasmatic triglycerides and cholesterol levels by 54 and 41 %, respectively, while the percentages of reduction were 43 and 30 %, respectively, with phthalimide. The hypocholesterolemic and hypotriglyceridemic activities of the (5g) derivative were similar to that obtained with the commercially available drug, pravastatin. The anti-inflammatory activity of compound (5b) was similar to ibuprofen and aspirin at 250 mg kg^?1. Taken together, it was demonstrated that the new phthalimide derivatives were able to increase HDL-cholesterol levels, along with reducing the cholesterol and triglyceride levels and carrageenan-induced edema in mice. Therefore, they may offer promise in the future as new hypolipidemic and anti-inflammatory agents.     

Synthesis, characterization, biological evaluation and in silico screening of oxadiazinanones

A series of novel oxadiazinan-5-one namely 2-methyl-2-phenyl-1,3,4-oxadiazinan-5-one (6), 2-(3-hydroxyphenyl)-2-methyl-1,3,4-oxadiazinan-5-one (7), 2-(4-hydroxyphenyl)-2-methyl-1,3,4-oxadiazinan-5-one (8), 2-(2,4-dihydroxyphenyl)-2-methyl-1,3,4-oxadiazinan-5-one (9) and 2-(2,5-dihydroxyphenyl)-2-methyl-1,3,4-oxadiazinan-5-one (10) have been synthesized by the reaction of acetophenone and its derivatives with cyanoacetic acid hydrazide. The structural assignments of the products were done on the basis of IR, ¹H NMR, ¹³C NMR, MS, and analytical data. The in vitro antioxidant and antimicrobial activity of all the synthesized compounds (6–10) was tested by the DPPH and disk diffusion method, respectively. The synthesized compounds were screened against Gram-positive and Gram-negative bacterial and fungal strains. Compound (7) showed the highest inhibition comparable with the standard antibiotic drugs Ciprofloxacin and Amphotericin B. The antibacterial activity of the synthesized compounds was further investigated with the help of in silico docking study using Discovery studio 3.1, Molego Virtual Docker and LigandScout to predict the active sites.     

Unsymmetrical 1,3-disubstituted urea derivatives as α-chymotrypsin inhibitors

The objective of this study was to synthesize potent and/or novel inhibitors for α-chymotrypsin activity. Eighteen derivatives of N-methylphenyl-N′-(alkyl/aryl) urea (1–18) were synthesized, and their inhibitory effects on α-chymotrypsin enzyme were evaluated. Two compounds exhibited potent inhibitory activities. The most potent, N-(2-methylphenyl)-2-oxo-1-pyrrolidinecarboxamide (15) having a methyl group at ortho position was the most active inhibitor with an IC₅₀ value of 8.10 ± 0.14 μM, which was comparable to standard chymostatin (IC₅₀ = 8.24 ± 0.11 μM). A slightly less potent, N-(2-acetylphenyl)-N′-(3-methylphenyl) urea (10), exhibited an IC₅₀ of 13.6 ± 0.23 μM. Compounds 3, 4, 7, 11, and 13 exhibited moderate activities. The results demonstrated that α-chymotrypsin inhibition is related to the position of the methyl group and the presence of substituent at the nitrogen of the urea bridge. The inhibitory trend suggests that α-chymotrypsin inhibitory activity declines with ortho > meta > para substitution order. In conclusion, our data suggest that the compound 15 may serve as a lead compound for further designing of other potent or novel α-chymotrypsin inhibitors.     

Antitumour activity of 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-substituted phenylprop-2-en-1-ylidene] pyrimidine-2,4,6(1H,3H,5H)-triones against Dalton’s ascitic lymphoma in mice

A new series of novel benzimidazole derivatives containing barbitone moiety (5a–f) was synthesized by a Knoevenagel condensation of (2E)-1-(1H-benzimidazol-2-yl)-3-phenylprop-2-en-1-ones (4a–f) and barbituric acid in the presence of catalytic amount of acetic acid medium. All the final structures were assigned on the basis of IR, ¹H NMR and mass spectra analysis. Acute toxicity studies were performed initially to determine the safety of titled derivatives and the ED ₅₀ value was calculated 50 mg/kg. All the final derivatives were screened for antitumour activity against Dalton’s ascitic lymphoma in mice. All the new candidates at a dose of 50 mg/kg showed a good antitumour activity against DLA-bearing mice when compared to the standard 5-fluro uracil. Among the final derivatives (5e), 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-(3-nitrophenyl) prop-2-en-1-ylidene] pyrimidine-2,4,6(1H,3H,5H)-trione was found to be most potent antitumour in nature.     

Synthesis,biological evaluation,and molecular modeling of (<Emphasis Type="Italic">E</Emphasis>)-2-aryl-5-styryl-1,3,4-oxadiazole derivatives as acetylcholine esterase inhibitors

A library of 2,5-disubstituted 1,3,4-oxadiazole derivatives of (E)-2-aryl-5-(3,4,5-trimethoxystyryl)-1,3,4-oxadiazoles 4(a–o) and (E)-2-aryl-5-(2-benzo[d][1,3]dioxol-5-yl)vinyl)-1,3,4-oxadiazoles 5(a–q) were synthesized and evaluated for their in vitro acetylcholinesterase (AChE) inhibitory activity. All the synthesized compounds exhibited moderate to good inhibitory activity toward the AChE enzyme. Among the oxadiazole derivatives examined, compounds 4a, 4g, 5c, and 5m (IC₅₀ values of 24.89, 13.72, 37.65, and 19.63 μM, respectively) were found to be promising inhibitors of AChE. Molecular protein–ligand docking studies were examined for these compounds using GOLD docking software and their binding conformations were determined and the simultaneous interactions mode was also established for the potent derivatives.     

α,α-Dibromoacetophenones mediated synthesis of some new 7H-7-alkoxy-3-alkyl/phenyl-6-aryl-s-triazolo[3,4-b][1,3,4]thiadiazines and their antimicrobial evaluation

A series of new 7H-7-alkoxy-3-alkyl/phenyl-6-aryl-s-triazolo[3,4-b][1,3,4]thiadiazines (3, 4) were synthesized by the reaction of various α,α-dibromoacetophenones 1 with 3-alkyl/phenyl-4-amino-5-mercapto-s-triazoles (2) in different alcoholic solvents in good yields. All the newly synthesized compounds (3, 4) were screened for their in vitro antibacterial and antifungal activity. Biological activities of these compounds were compared with those of the commercially available antibiotic, ciprofloxacin and antifungal agent, amphotericin-B. The title compounds showed good activity against the Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis and the yeasts, Saccharomyces cerevisiae and Candida albicans.     

Synthesis of some novel C-5 and N-3 substituted 2-(2-hydroxyphenylimino)thiazolidin-4-one derivatives with broad-spectrum antimicrobial activity

In the present article, compounds 5-((substituted-2-chloroquinolin-3-yl)methylene)-2-(2-hydroxyphenylimino)thiazolidin-4-ones (3a–k), 1-(2-(2-(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (6) and 1-(2-(5-((substituted-2-chloroquinolin-3-yl)methylene)-2-(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-triones (8a–k) have been synthesized by substituting C-5 and N-3 position of parent compound 2-(2-hydroxyphenylimino)thiazolidin-4-one (1). Structures of the newly synthesized compounds were assigned on the basis of elemental analyses, IR, ¹H NMR, ¹³C NMR, and mass spectra. In vitro antimicrobial activity of target compounds (3a–k, 6 and 8a–k) was investigated against two Gram-positive, two Gram-negative bacteria and three fungal strains. Among the tested compounds (3e), (3f), and (3h) showed very good antifungal activity, while compound (6) showed very good antibacterial activity. Compounds (8e), (8f), and (8h) showed excellent antifungal and antibacterial activities.     

Mannich base derivatives of 1,3,4-oxadiazole: synthesis and screening against Entamoeba histolytica

Mannich base derivatives of 5-(pyridine-4-yl)-1,3,4-oxadiazole-2-(3H)-thione with substituted piperazine were synthesized and characterized. In vitro antiamoebic activity was performed against HM1: IMSS strain of Entamoeba histolytica and the cytotoxicity of the compounds having IC₅₀ value less than metronidazole was assessed by MTT assay on human breast cancer MCF-7 cell line. The results revealed that compounds 2, 3 and 5 were found to be better inhibitors of E. histolytica than the reference drug metronidazole and found low cytotoxic in the concentration range of 2.5–250 μM. This study suggests the possibility of developing 1,3,4-oxadiazole analogues as potential drug candidates.     

Preparation and antimicrobial activity evaluation of some new bi- and triheterocyclic azoles

Synthesis of the carbothioamides (5, 13, 22) was performed starting from 3H-1,2,4-triazol-3-ones (2, 17) by several steps, and then, these carbothioamides was converted to triheterocyclic compounds incorporating 1,2,4-triazole, imidazole and 1,3-thiazol(idinone) moieties. The reaction of compound 2 with 3,4-difluoronitrobenzene afforded the 2-(2-fluoro-4-nitrophenyl) derivative, 10. Compound 10 was converted to the arylideneamino derivatives (12a, b) via the reduction of nitro group. On the other hand, the treatment of the hydrazide (20) that was obtained starting from 17, with several aromatic aldehydes generated the corresponding arylidenhydrazides (21a–c). Mannich reaction between compound 2 and a suitable heterocyclic amine resulted in the N-alkylation of 2. All newly synthesized compounds were screened for their antimicrobial activities. In general, most compounds except 22 were Found (%) to be active against Mycobacterium smegmatis, Candida albicans and/or Saccharomyces cerevisiae. Furthermore, 9a and b, which are Mannich bases incorporating morpholine or piperazine nucleus, exhibited excellent antimicrobial activity on test microorganisms. In addition, the hydrazide, 4, was Found (%) to have activity towards Ec and Yp.     

Synthesis and antidepressant activity of di substituted-5-aryl-1,2,4-triazoles

A series of 5-aryl-1H-1,2,4-triazole-3-thiol (3) were synthesized. Alkylation of thiol group with N,N-dimethyl/diethyl/dicyclo hexyl-(2-chloro ethyl) amine gave compounds N,N-disubstituted-2-(5-aryl-1H-1,2,4-triazol-3-ylthio)ethanamine (4). These compounds were characterized on the basis of IR, ¹H NMR, Mass spectral data, and elemental analysis. The newly synthesized compounds were screened for their antidepressant activity by using tail suspension test in mice.