Synthesis and anti‐HIV activity of new 2‐thiolumazine and 2‐thiouracil metal complexes

A series of new Cu(II), Pt(II), VO(II), Fe(II), and Co(II) complexes ( 1‐‐5 ) with 3‐methyl‐6,7‐diphenyllumazine are described. Similarly, complexes from 2‐thiouracil with Cu(II) ( 6,7 ) and Pt(II) ( 8 ) have been prepared and characterized by spectroscopic methods. All the complexes were assayed for their anti‐HIV‐1 and HIV‐2 activity by examination of their inhibition of HIV‐induced cytopathogenicity in MT‐4 cells. Compound 3 was found to be the most active inhibitor against HIV‐2 in cell culture (EC₅₀ = >18.9 μ g/mL, selectivity index (SI) = 3), which provided a good lead for further optimization. Compounds 6 and 7 exhibited some activity (EC₅₀ = >7.12 μ g/mL and >2.23 μ g/mL) against HIV‐1 and HIV‐2, but no selectivity was observed (SI <1). © 2010 Wiley Periodicals, Inc. Heteroatom Chem 22:44–50, 2011; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20654     

Synthesis and antibacterial evaluation of some new 4‐substituted‐3‐aryl‐1‐(2,6‐dimethylpyrimidin‐4‐yl)pyrazoles

Synthesis of a series of new 4‐substituted‐3‐aryl‐1‐(2,6‐dimethylpyrimidin‐4‐yl)pyrazoles ( 2a , 2b , 2c , 2d , 2e , 2f , 2g , 3a , 3b , 3c , 3d , 3e , 3f , 3g , and 4a , 4b , 4c , 4d , 4e , 4f , 4g ) is described. All the synthesized compounds were evaluated in vitro for their antibacterial activity against two gram‐positive and two gram‐negative bacteria, namely, Bacillus subtilis (MTCC 8509), Bacillus stearothermophilus (MTCC 8508), Escherichia coli (MTCC 51), and Pseudomonas putida (MTCC 121), and their activity was compared with two commercial antibiotics, streptomycin and chloramphenicol. Two compounds, namely, 3‐(4‐anisyl)‐1‐(2,6‐dimethylpyrimidin‐4‐yl)pyrazole‐4‐carboxaldehyde ( 2b ) and 3‐(2‐thienyl)‐1‐(2,6‐dimethyl pyrimidin‐4‐yl)pyrazole‐4‐carboxaldehyde ( 2g ) were found to be equipotent to streptomycin and chloramphenicol against gram‐negative bacteria, E. coli having minimum inhibitory concentration (MIC) value = 4 μg/mL. Compounds 4b and 4d also displayed good activity against E. coli with MIC = 8 μg/mL. J. Heterocyclic Chem., (2011).     

Novel 5‐Methyl‐2‐[(un)substituted phenyl]‐4‐{4,5‐dihydro‐ 3‐[(un)substituted phenyl]‐5‐(1,2,3,4‐tetrahydroisoquinoline‐2‐yl)pyrazol‐1‐yl}‐oxazole Derivatives: Synthesis and Anticancer Activity

Eleven novel 5‐methyl‐2‐[(un)substituted phenyl]‐4‐{4,5‐dihydro‐3‐[(un)substituted phenyl]‐5‐(1,2,3,4‐tetrahydroisoquinoline‐2‐yl)pyrazol‐1‐yl}‐oxazole derivatives were synthesized and characterized by elemental analysis, ESI‐MS, ¹H NMR and ¹³C NMR. All of the compounds have been screened for their antiproliferative activities against PC‐3 cell (human prostate cancer) and A431 cell (human epidermoid carcinoma cancer) lines in vitro. The results revealed that compounds 4g , 4j and 4k exhibited the strong inhibitory activities against the PC‐3 cell lines (with IC₅₀ values of 2.8±0.11, 3.1±0.10 and 3.0±0.06 μg/mL, respectively).     

Synthesis,characterization and studies of new 3‐benzyl‐4H‐1,2,4‐triazole‐5‐thiol and thiazolo[3,2‐b][1,2,4]triazole‐5(6H)‐one heterocycles

3‐Benzyl‐4‐phenyl‐1,2,4‐triazole‐5‐thiol ( 1 ) was synthesized and used as starting material for preparation of 1,2,4‐triazole bearing substituted thiosemicarbazides moiety ( 4a‐d ) in high yields. The thiosemicarbazides 4a‐d were cyclized in basic medium to give two triazole rings linked by thiomethylene group ( 5a‐d ), while cyclization of thiosemicarbazides 4a‐d with chloroacetyl chloride in the presence of CHCl₃ and K₂CO₃ afforded the thiazolidinone derivatives 6a‐d . The reaction of thiosemicarbazides 4a‐c with phenacyl bromide in the presence of EtOH and fused CH₃COONa gave the corresponding thiazoline ring systems 7a‐c . Condensation of the 3‐benzyl‐1,2,4‐triazole‐5(1H)‐thiol ( 1 ) with chloroacetic acid and aromatic aldehydes ( 8a‐ g) in boiling acetic acid/acetic anhydride mixture in the presence of fused sodium acetate gave one single isomer only, which might be 9a‐g or 10a‐g . Upon application of Micheal addition reaction on compounds 9a‐e with cyclic secondary amines such as piperidine or morpholine the 2‐benzyl‐6‐(α‐amino‐aryl/methyl)‐1,3‐thiazolo[3,2‐ b][1,2,4]‐triazol‐5‐ols ( 11a‐j ) were obtained in good yields The structure of all new compounds were determined using both spectral and elemental analyses.     

Design,Synthesis, and Herbicidal Activities of 3‐Aryl‐4‐substituted‐5‐[3‐(trifluoromethyl)phenoxy]‐1,2,4‐triazoles

In order to find novel bleaching herbicide lead compounds, a series of novel 3‐aryl‐4‐substituted‐5‐[3‐(trifluoromethyl)phenoxy]‐1,2,4‐triazoles were designed and synthesized by the multi‐step reactions. N‐(Arylformamido)phenylthioureas undergo ring closure in the presence of sodium hydroxide to generate 3‐aryl‐4‐substituted‐4H‐[1,2,4]triazol‐5‐thiols 1 , which reacted with methyl sulfate in the presence of K₂CO₃ to give 3‐aryl‐5‐methylsulfanyl‐4‐substituted‐4H‐[1,2,4]triazoles 2 . The target compounds 4 were synthesized by the oxidation of 2 in the presence of H₂O₂ and Na₂WO₄, followed by the substitution with 3‐(trifluoromethyl)phenol in moderate to good yields. Their structures were confirmed by IR, ¹H NMR, EI–MS, and elemental analyses. The preliminary bioassay indicated that some of them displayed moderate to good selective herbicidal activity against Brassica campestris L at the concentration of 100 µg/mL. Compounds 4c and 4i possessed 75.0% and 82.6% inhibition against Brassica campestris L at the concentration of 100 µg/mL. However, the target compounds 4 showed weak herbicidal activity against Echinochloa crus‐galli at the concentration of 100 and 10 µg/mL.     

Synthesis and Antiviral Bioactivity of Novel 2‐Substituted Methlthio‐5‐(4‐Amino‐2‐Methylpyrimidin‐5‐yl)‐1,3,4‐Thiadiazole Derivatives

A series of novel 2‐substituted methlthio‐5‐(4‐amino‐2‐methylpyrimidin‐5‐yl‐)‐1,3,4‐thiadiazole derivatives were synthesized, characterized and evaluated for antiviral activities against tobacco mosaic virus (TMV). The preliminary biological results indicated that most compounds exhibit excellent antiviral activity against TMV in vivo. Among these compounds, compounds 9c , 9i , and 9p displayed the similar curative effect against TMV (EC₅₀ = 287.05–322.47 µg/mL) to that of the commercial agent Ningnanmycin (EC₅₀ = 301.83 µg/mL). In particular, compound 9d demonstrated the best curative effect against TMV (EC₅₀ = 266.21 µg/mL), which was better than that of commercial Ningnanmycin.     

Synthesis and antimicrobial evaluation of new 1‐{[4‐(4‐Halogenophenyl)‐4H‐1,2,4‐ triazol‐3‐yl]sulfanyl}acetyl‐4‐substituted thiosemicarbazides and products of their cyclization

By the reaction of hydrazides of 4‐(4‐halogenophenyl)‐4H‐1,2,4‐triazol‐3‐yl‐sulfanyl acetic acid with isothiocyanate, 1‐acyl‐4‐substituted thiosemicarbazide derivatives ( 7–19 ) were obtained. The cyclization of compounds ( 7–19 ) in the presence of 2% NaOH led to the formation of compounds ( 20–26 ) containing two 1,2,4‐triazole rings connected by a methylenesulfanyl group. The new compounds were tested for their in vitro antimicrobial activity. Some of the tested compounds ( 9, 12, 18, 21, 22 ) showed activity against the reference strains of Gram‐positive bacteria with the MIC (minimal inhibitory concentration) = 125 to >1000 μg/mL. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 23:117–121, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20758     

Synthesis of novel spiro(indolone‐3,2′‐[1,3,4]thiadiazol)‐2‐ones and evaluation of their antidepressant and anticonvulsant activities

The reaction of 3‐(dicyanomethylene)‐2‐indolone in a solution of ethanol/piperidine with 4‐substituted thiosemicarbazides forms the derivatives of 5′‐(substituted amino)‐3′H–spiro(indoline‐3,2′‐[1,3,4]thiadiazol‐2‐one. Rationales for these conversions involving the nucleophilic addition on the dicyanomethylene carbon atom are presented. The prepared compounds were evaluated each for antidepressant activity using tail suspension behavioral despair test and anticonvulsant activity against pentylenetetrazol induced seizures in mice. J. Heterocyclic Chem., (2011).     

Design,synthesis, and biological activity of novel 2‐(pyridin‐3‐yl)ethan‐1‐one oxime ethers bearing adamantane moiety

With the aim of discovering a lead compound for pyridine‐based fungicide bearing adamantane moiety, a series of novel O‐alkyl/benzyl‐1‐(adamantan‐1‐yl)‐2‐(pyridin‐3‐yl)ethan‐1‐one oximes were synthesized from 3‐methylpyridine, ethyl (adamantan‐1‐yl)carboxylate, and alkoxyamine or benzoxyamine hydrochloride. The in vitro antifungal activity against four pathogenic fungi was evaluated, and some compounds exhibited good antifungal activity. Compounds 3d and 3f demonstrated strong activity against Sclerotinia sclerotiorum, with EC₅₀ values of 11.25 and 12.87 μg/mL, respectively; 3b , 3c, and 3k had notable activity against Botrytis cinerea, with EC₅₀ values of 12.78, 12.57, and 11.97 μg/mL, respectively. For Rhizoctonia Solani, 3d and 3g showed sufficient activity with EC₅₀ values of 9.66 and 8.90 μg/mL, respectively. In addition, 3d and 3g demonstrated moderate activity against Colletotrichum orbiculare, with EC₅₀ values of 14.32 and 15.83 μg/mL, respectively.     

Design,Synthesis, and in vitro Antimicrobial Activity of New Furan/Thiophene‐1,3‐Benzothiazin‐4‐one Hybrids

This study presents the design, synthesis, spectral analysis, and in vitro antimicrobial evaluation of a new series of furan/thiophene‐1,3‐benzothiazin‐4‐one hybrids ( 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ). New compounds were obtained by cyclization reaction of N‐substituted furan/thiophene‐2‐carboxamide derivatives ( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ) with thiosalicylic acid. All synthesized compounds were screened for their in vitro antimicrobial activities using the broth microdilution method. Nine of the synthesized compounds showed good activity against Gram‐positive, Gram‐negative bacteria, and yeasts belonging to Candida spp. (MIC = 7.81–500 μg/mL), especially against Staphylococcus spp. (MIC = 15.62–62.5 μg/ml), Bacillus spp. (MIC = 7.81–62.5 μg/mL), Bordetella bronchiseptica ATCC 4617 (MIC = 62.5–125 μg/mL), and fungistatic activity against Candida spp. (MIC = 62.5–125 μg/mL).     

Synthesis of New (Pyrazol‐3‐yl)‐1,3,4‐oxadiazole Derivatives by Unexpected Aromatization During Oxidative Cyclization of 4,5‐Dihydro‐1H‐pyrazole‐3‐carbohydrazones and Their Biological Activities

A series of novel 2‐(4‐(4‐chlorophenyl)‐1H‐pyrazol‐3‐yl)‐5‐(Aryl)‐1,3,4‐oxadiazoles were synthesized by unexpected aromatization during oxidative cyclization of 4‐(4‐chlorophenyl)‐4,5‐dihydro‐1H‐pyrazole‐3‐carbohydrazones using chloramine‐T as an oxidant. The hydrazones were derived from 4‐(4‐chlorophenyl)‐4,5‐dihydro‐1H‐pyrazole‐3‐carbohydrazide and various substituted aldehydes. The structure of the synthesized compounds was confirmed by FTIR, ¹H NMR, ¹³C NMR, and mass spectral data. The synthesized compounds were evaluated for their antitubercular and antioxidant activities. All the compounds 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h and 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h showed good antitubercular activity against Mycobacterium tuberculosis (minimum inhibitory concentration = 25 µg/mL for 4f and 4g , 50–100 µg/mL for the rest). However, all the compounds exhibited poor antioxidant activity against 1,1‐diphenyl‐2‐picryl‐hydrazil free radical.     

Efficient Synthesis of Novel 3‐Phenyl‐5‐thioxo‐3,4,5,6‐tetrahydroimidazo[4,5‐c]pyrazole‐2(1H)‐carbothioamide Derivatives Using a CeO2–MgO Catalyst and Evaluation of Antimicrobial Activity

Imidazo[4,5‐c ]pyrazole derivatives ( 3a–f , 4a–f , and 5a–f ) were efficiently synthesized by one‐pot three‐component reactions using CeO₂–MgO as the catalyst. The synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, and mass spectroscopic analyses. The in vitro antimicrobial activity of the synthesized compounds against various bacterial and fungal strains was screened. Compound 3b was highly active [minimum inhibitory concentration (MIC): 0.5 μg/mL] against Gram‐positive Staphylococcus aureus , and compounds 3b , 3f , 4d , and 4e were highly active (MIC: 0.5, 2, 2, and 0.5 μg/mL, respectively) against Gram‐negative Pseudomonas aeruginosa and Klebsiella pneumoniae , relative to standard ciprofloxacin in the antibacterial activity screening. Compounds 3b and 4f were highly active (MIC: 4 and 0.5 μg/mL, respectively) against Aspergillus fumigatus and Microsporum audouinii in the antifungal activity screening compared with the clotrimazole standard.     

Synthesis and Antimicrobial Activities of Novel 2‐[substituted‐1H‐pyrazol‐4‐yl] Benzothiazoles,Benzoxazoles, and Benzimidazoles

In an endeavor to find a new class of antimicrobial agents, a series of novel substituted benzimidazole, benzoxazole, and benzothiazole derivatives 6 containing pyrazole moiety have been synthesized by reaction of 3‐aryl‐4‐formyl pyrazole 4 with substituted phenylenediamine or o‐aminophenol or o‐aminothiophenol 5 . Reaction of phenyl hydrazine or 2‐hydrazinopyridine 1 with substituted acetophenones 2 gave the corresponding hydrazones 3 , which on Vilsmeier–Haack reaction with POCl₃–DMF gave substituted 3‐aryl‐4‐formyl pyrazoles 4 . All final compounds 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h , 6i , 6j , 6k were evaluated for in vitro antibacterial activities against Escherichia coli and Staphylococcus aureus strains and in vitro antifungal activity against Candida albicans and Aspergillus niger strains by using serial dilution method. The antimicrobial activities were expressed as the minimum inhibitory concentration in µg/mL. The compound containing benzimidazole and benzoxazole moiety gave better antibacterial and antifungal activities than benzothiazole compounds.     

Synthesis,Anticancer Evaluation,and Molecular Docking Studies of Novel (4‐Hydroxy‐2‐Thioxo‐3,4‐Dihydro‐2H‐[1,3]Thiazin‐6‐Yl)‐Chromen‐2‐Ones via a Multicomponent Approach

A series of coumarin‐substituted 1,3‐thiazine‐2‐thione derivatives ( 4a–m ) were synthesized via the multicomponent reaction of 3‐chloro‐3‐(2‐oxo‐2H‐chromen‐3‐yl)acrylaldehyde ( 1 ) carbon disulfide ( 2 ), and various primary amines ( 3 ), in presence of triethylamine and acetonitrile under stirring with good yields. The structures of all the synthesized compounds were characterized by analytical and spectral studies. Further, the synthesized compounds were screened for their in vitro antiproliferative activities against different cancer cell lines (A549, MDA‐MB‐231, MCF7, HeLa, and B16F10). Studies on the molecular interactions to recognize the hypothetical binding motif of the title compounds with the target Hsp 100 were carried out employing the Schrodinger software. Compounds 4a , 4c and 4m showed activity against all the five cell lines compared with the reference drug, and 4a exhibited the least IC₅₀ concentration of 7.56 ± 1.07 μg/mL against MCF7. This in vitro anticancer result was supported by in silico docking and in silico ADME (absorption, distribution, metabolism, and excretion) studies as well.     

Synthesis of 2,6‐diamino‐5‐[(2‐substituted phenylamino)ethyl]pyrimidin‐4(3h)‐one as inhibitors of folate metabolizing enzymes

A series of eleven novel 2,6‐diamino‐5‐[(2‐substituted phenylamino)ethyl]pyrimidin‐4(3H)‐one derivatives were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS). The synthesis of analogues 2a‐f, 3a and 3e was achieved via an improved method. Commercially available anilines 12a‐f were used as starting materials which on reaction with chloroacetaldehyde followed by cyanoacetate and cyclocondensation with guanidine afforded 2,6‐diamino‐5‐[(2‐substituted phenylamino)ethyl]pyrimidin‐4(3H)‐one 2a‐f in three steps. The N‐methyl analogues 3a‐3e were prepared by reductive methylation. These compounds were evaluated against dihydrofolate reductase from Escherichia coli, Toxoplasma gondii, Pneumocystis carinii, human, and rat liver. Few compounds were marginally active against dihydrofolate reductase. The most potent inhibitor, ( 2c ) which has a 1‐naphthyl substituent on the side chain, has an IC₅₀ = 150 μM and 9.1 μM against Escherichia coli and Toxoplasma gondii DHFR, respectively.     

3‐Aryl‐5‐furylpyrazolines and their biological activities

Aryl‐furyl substituted pyrazolines 2a–c and 4a–c were prepared by the reaction of α,β‐unsaturated carbonyl compounds with hydrazine or phenyl hydrazine. N‐chloroacetyl derivatives 3a–c were obtained by the N‐acetylation of 2a–c . The antibacterial activities of synthesized pyrazolines were examined by employing the disk‐diffusion technique. All synthesized compounds showed antibacterial effects in 1200 μg concentration. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:345–347, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10159     

Synthesis and in vitro antibacterial evaluation of 1‐substituted‐4‐ethoxycarbonylmethylthiosemicarbazides and products of their dehydrocyclization

A series of s‐triazoles and thiohydantoines were synthesized by dehydrocyclization of 1‐substituted‐4‐ethoxycarbonylmethylthiosemicarbazides. The molecular structure proposed for s‐triazoles was confirmed by the X‐ray crystal structure analysis of one compound that was prone to crystallization. All compounds were tested in vitro for their antibacterial activity. Some of them showed low levels of activity against Gram‐positive species, MIC range 100–400 μg/mL or higher. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:131–138, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20597     

Synthesis and Antiproliferative Evaluation of 2′‐Arenesulfonyloxy‐5‐benzylidene‐thiazolidine‐2,4‐diones

A series of 2′‐arenesulfonyloxy‐5‐benzylidene‐thiazolidine‐2,4‐diones (TZDs) were synthesized and examined for their antiproliferative effects on a panel of carcinoma cell lines. Our results indicated that initial synthesis of 5‐[2′‐hydroxybenzylidene]‐2,4‐thiazolidinone (9) by Knoevenagel condensation followed by nucleophilic substitution with arylsulfonyl chlorides exhibited superior efficiency to the alternative synthetic route. Among tested compounds, only 8c and 8e showed significant antiproliferative activity against PC‐3 and BT474 cells with GI₅₀ values of 8.4 and 20.6 μM, respectively. SKHep cells displayed interesting structure‐activity relationships in response to TZD derivatives treatment. Alkyl group‐substituted TZD analogs such as 8a (4‐Me, GI₅₀, 9.4 μM) and 8k (4‐iso‐propyl, GI₅₀, 9.8 μM) revealed better antiproliferative activity than those with bulkier alkyl groups. On the other hand, halogen‐substituted TZD analogs 8c, 8h, and 8i showed better antiproliferative activity against H460 cell line. Together, the new synthesized TZD derivatives 8a , 8b , 8c , 8d , 8e , 8f , 8g , 8h , 8i , 8j , 8k , 8l , 8m , 8n , 8o , 8p exhibited appreciable antiproliferative activity worth for further study.     

Synthesis and Antifungal Activity Evaluation of Novel Substituted Pyrimidine‐5‐Carboxamides Bearing the Pyridine Moiety

A series of novel N‐(substituted phenyl/benzyl)‐2‐methylthio‐4‐((pyridin‐3‐ylmethyl)amino)pyrimidine‐5‐carboxamides were synthesized by multistep reactions. The structures of the target compounds were characterized by IR, ¹H NMR, ¹³C NMR, and elemental analysis. Their in vitro antifungal activities against two kinds of plant pathogenic fungi were evaluated by the mycelial growth rate method. The result showed that at the dosage of 100 μg/mL, several of these compounds exhibited moderate activity against Botrytis cinerea with inhibition rates of ~70%, and most compounds (e.g., 5a , 5c , 5e , 5f, and 5h ) possessed excellent activity against Sclerotinia Sclerotiorum with more than 90% inhibition rate.