Stereoselective Synthesis and Antiviral Activity of (1E,2Z,3E)‐1‐(Piperidin‐1‐yl)‐1‐(arylhydrazono)‐2‐[(benzoyl/benzothiazol‐ 2‐oyl)hydrazono]‐4‐(aryl1)but‐3‐enes

The reaction of benzoyl hydrazine 1a or benzothiazole‐2‐carbohydrazide 1b with 2‐oxo‐N‐arylpropanehydrazonoyl chlorides 2a–d yielded (1Z,2E)‐2‐[(benzoyl/benzothiazol‐2‐oyl)hydrazono]‐N‐(aryl)propanehydrazonoyl chlorides 3a–e . The reaction of 3a–c with sodium benzenesulphinate furnished sulphones 5a–c while the reaction of 5d , e with hydroxyl amine afforded hydroxomoyl derivatives 6a , b . The one‐pot sterioselective reaction of N‐(aryl)propanehydrazonoyl chlorides 3 with certain aromatic aldehydes in the presence of piperidine resulted in the formation of (1E,2Z,3E)‐1‐(piperidin‐1‐yl)‐1‐(arylhydrazono)‐2‐[(benzoyl/benzothiazol‐2‐oyl)hydrazono]‐4‐(aryl¹)‐but‐3‐enes 7a–g . X‐ray analysis of piperidinyl amidrazone 7g showed a conversion of its geometrical structure with respect to that of compound 3 and confirmed the stereoselectivity of the latter reaction. The piperidinyl amidrazones 7a–g possessed a significant antiviral activity against herpes simplex viruses (HSV‐1). Compound 7d reduced the number of viral plaques of herpes simplex type‐1 (HSV‐1) by 67%, with respect to the effect of reference drug Aphidicolin.     

Synthesis and X‐ray study of the 6‐(N‐pyrrolyl)purine and thymine derivatives of 1‐aminocyclopropane‐1‐carboxylic acid

Abstract: The novel purine and pyrimidine derivatives of 1‐aminocyclopropane‐1‐carboxylic acid 1 and 2 were obtained by alkylation of 6‐(N‐pyrrolyl)purine and thymine with methyl 1‐benzamido‐2‐chloromethylcyclopropanecarboxylate. X‐ray crystal structure analysis shows that the cyclopropane rings in 1 and 2 posses Z‐configuration. The cyclopropane ring atoms and attached atoms of the benzamido and methoxycarbonyl moiety of both molecules are disposed perpendicularly to each other. The carbonyl oxygen of the methoxycarbonyl moiety adopts in both compounds a synperiplanar conformation with respect to the midpoint of the distal bond of the cyclopropane ring. The torsion angles φ and ψ for the 1‐aminocyclopropane‐1‐carboxylic acid residue in 1 and 2 correspond to a folded conformation, while the torsion angles ω define antiperiplanar conformation. Intermolecular hydrogen bonds connect the molecules of 1 into dimers. Each dimer is hydrogen‐bonded with four ethanol molecules, thus forming discrete unit. On the contrary, intermolecular hydrogen bonds link the molecules of 2 generating three‐dimensional network.     

Synthesis and pharmacological evaluation of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones as analgesic and anti‐inflammatory agents

A new series of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one with different aldehydes and ketones. The compounds were investigated for their analgesic activity in albino mice, and for their anti‐inflammatory and ulcerogenic activities in Wistar rats. All test compounds exhibited analgesic and anti‐inflammatory activities. Compound VA2 (2‐(1‐ethylpropylidene‐hydrazino)‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent analgesic activity and compound VA3 (2‐(1‐methylbutylidene‐hydrazino)‐3‐(4‐chlorophenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent anti‐inflammatory activity when compared with the reference standard, diclofenac sodium. The test compounds showed only mild ulcerogenic side effects when compared with aspirin. Drug Dev Res 69: 226–233, 2008 ©2008 Wiley‐Liss, Inc.     

Design,Synthesis, and Antitumor Activity of (E,Z)‐1‐(dihydrobenzofuran‐5‐yl)‐3‐phenyl‐2‐(1,2,4‐triazol‐1‐yl)‐2‐propen‐1‐ones

A series of (E,Z)‐1‐(dihydrobenzofuran‐5‐yl)‐3‐phenyl‐2‐(1,2,4‐triazol‐1‐yl)‐2‐propen‐1‐ones ( C1 – C35 ) were designed and synthesized, and the structures of compounds (Z)‐ C27 and (Z)‐ C29 were confirmed by single‐crystal X‐ray diffraction. The antitumor activities of these novel compounds against cervical cancer (HeLa), lung cancer (A549), and breast cancer (MCF‐7) cell lines were evaluated in vitro. Majority of the title compounds exhibited strong antitumor activities and were much more promising than the positive control Taxol, which were also accompanied by lower cytotoxicity to normal cells. In particular, compounds (E,Z)‐ C24 exhibited the most consistent potent activities against three neoplastic cells with IC₅₀ values ranging from 3.2 to 7.1 μm . Further researches demonstrated that compounds (E,Z)‐ C24 could induce cell apoptosis and arrest cell cycle at the G2/M and S phases. Meanwhile, the structure–activity relationship between the configurations and cytotoxicity of the compounds was also investigated.     

Synthesis and in‐vitro Antimycobacterial Evaluation of 1‐(Cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐ 8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids

Fifty one newer 1‐(cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids were synthesized from 1,3‐dichloro‐2‐methylbenzene and evaluated for in‐vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi‐drug resistant Mycobacterium tuberculosis (MDR‐TB), and Mycobacterium smegmatis (MC²). Among the synthesized compounds, 1‐cyclopropyl‐1,4‐dihydro‐7‐(3,4‐dihydro‐6,7‐dimethoxyisoquinolin‐2(1H)‐yl)‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9p was found to be the most active compound in vitro with a MIC value of 0.39 μM against MTB. Against MDR‐TB, compound 7‐(2‐carboxy‐5,6‐dihydroimidazo[1,2‐a]pyrazin‐7(8H)‐yl)‐1‐cyclopropyl‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9n was found to be the most active with a MIC value of 0.09 μM.     

Synthesis of carbon‐14 labeled 4‐[4‐[2‐[2‐[bis(4‐chlorophenyl) methoxy]ethyl sulfonyl][1‐14C]ethoxy]phenyl]‐1,1,1‐trifluoro‐2‐butanone

Carbon‐14 labeled 4‐[4‐[2‐[2‐[bis(4‐chlorophenyl)methoxyethylsulfonyl] [1‐¹⁴C]ethoxy]phenyl]‐1,1,1‐trifluoro‐2‐butanone was prepared in a six step radioactive synthesis from 2‐bromo[1‐¹⁴C]acetic acid. The overall radiochemical yield was 2.2%. The specific activity of the final product was found to be 42μCi/mg with a radiochemical purity of >98%. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis,Polymorphism, and Insecticidal Activity of Methyl 4‐(4‐chlorophenyl)‐8‐iodo‐2‐methyl‐6‐oxo‐1,6‐dihydro‐4H‐pyrimido[2,1‐b]quinazoline‐3‐Carboxylate Against Anopheles arabiensis Mosquito

Mosquitoes are the major vectors of pathogens and parasites including those causing malaria, the most deadly vector‐borne disease. The negative environmental effects of most synthetic compounds combined with widespread development of insecticide resistance encourage an interest in finding and developing alternative products against mosquitoes. In this study, pyrimido[2,1‐b]quinazoline derivative DHPM 3 has been synthesized by three‐step chemical reaction and screened for larvicide, adulticide, and repellent properties against Anopheles arabiensis, one of the dominant vectors of malaria in Africa. The title compound emerged as potential larvicide agent for further research and development, because it exerted 100% mortality, while adulticide activity was considered moderate.     

Synthesis and Anticonvulsant Activity of New N‐(Alkyl/Sub‐stituted aryl)‐N′‐[4‐(5‐cyclohexylamino)‐1,3,4‐thiadiazole‐2‐yl)phenyl]thioureas

A series of novel thiourea derivatives carrying the 5‐cylohexylamino‐1,3,4‐thiadiazole moiety was synthesized and their anticonvulsant activity was evaluated. Structures of the synthesized compounds have been confirmed by IR, ¹H‐NMR, and elemental analysis. All of the compounds were administered at a dose of 50 mg/kg. Some of the active compounds have different effects in pentylenetetrazole (PTZ) and maximal electroshock (MES) tests, indicating the therapeutical potential in petit mal seizures, but not in grand mal seizures. Compounds 10 , 11 , 13 , and 14 carrying 2‐methylphenyl, 4‐chlorophenyl, allyl, and 4‐methylphenyl on the thiourea pharmacophore, increased the survival rate in the PTZ model. The ED₅₀ values of the active compounds 10 , 11 , 13 , and 14 were found 68.42, 43.75, 18.75 and 25 mg/kg, respectively.     

Facile Synthesis and In‐Vitro Antitumor Activity of Some Pyrazolo[3,4‐b]pyridines and Pyrazolo[1,5‐a]pyrimidines Linked to a Thiazolo[3,2‐a]benzimidazole Moiety

The key precursor E‐3‐(N,N‐dimethylamino)‐1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)prop‐2‐en‐1‐one 4 was synthesized in good yield using Gold's reagent. The reaction of enaminone 4 with 5‐amino‐3‐aryl‐1‐phenylpyrazoles 5a , b in refluxing acetic acid in the presence of sulphuric acid, yielded pyrazolo[3,4‐b]pyridines 7a , b . Similarly, pyrazolo[1,5‐a]pyrimidines 10a , b and 14a – f were prepared by reaction of enaminone 4 with 5‐amino‐1H‐pyrazoles 8a , b and 12a – f , respectively. The structure of pyrazolo[1,5‐a]pyrimidine 10b was determined by X‐ray diffraction. The synthesized compounds were tested for their in‐vitro antitumor activity against the colon cancer cell line CaCo‐2; their cytotoxicity against the normal fibroblast cell line BHK was explored as well. Some of the tested compounds exhibited cell growth inhibitory activity. The significant antitumor activity of compound 14f against the CaCo‐2 cell line (IC₅₀ = 0.5 μg/mL) was coupled with a lower toxicity against BHK (IC₅₀ = 2.3 μg/mL).     

Synthesis and Evaluation of 2‐Alkylthio‐4‐(N‐substituted sulfonamide)pyrimidine Hydroxamic Acids as Anti‐myeloma Agents

A series of pyrimidine hydroxamic acids with a sulfide substituent at the second position and a sulfonamide substituent at the fourth position have been synthesized and evaluated for their activity against human myeloma cell line RPMI 8226. Several compounds exhibited significant anti‐cancer potency. It was found that representative compound 6a selectively killed cancerous but not normal cells. Moreover, compound 6a was effective in causing apoptosis in RPMI 8226 cells and exhibited promising HDAC‐inhibitory activities.     

Synthesis of 2‐(methylsulfonyl)‐5‐(4‐(methylsulfonyl) phenyl)‐4‐phenyl‐1H‐[5‐14C]imidazole,a selective COX‐2 inhibitor,via asymmetrical benzoins

4,5‐Diarylimidazoles labeled with carbon‐14 in the 5‐position of the imidazole ring were prepared as a part of three‐step sequence from 2‐hydroxy‐1‐(4‐(methylthio)phenyl)‐2‐phenyl[1‐¹⁴C]ethanone as a key synthetic intermediate which has been synthesized from potassium [¹⁴C]cyanide.     

Fungicide Activity of 5‐(4‐Chlorobenzylidene)‐(Z)‐2‐dimethylamino‐1,3‐thiazol‐4‐one against Cryptococcus Neoformans

The present work describes the synthesis and antifungal evaluation of new 5‐arylidene‐(Z)‐2‐dimethylamino‐1,3‐thiazol‐4‐ones 4a – f , obtained by the reaction of aromatic aldehydes 1 and rhodanine 2 followed by treatment with DMF. All compounds were tested against a panel of yeasts, hialohyphomycetes, and dermatophytes using the microbroth dilution method. Compounds 4a and 4c showed antifungal activity, with compound 4a being the most active one. Compound 4a demonstrated to be fungicidal rather than fungistatic and selective activity against Cryptococcus neoformans and dermatophytes. MIC₁₀₀, MIC₈₀, and MIC₅₀ of 4a were determined against a panel of clinical isolates of C. neoformans showing ranges of MICs between 2 and 16 μg/mL.     

Synthesis,molecular docking,and pharmacological evaluation of N‐(2‐(3,5‐dimethoxyphenyl)benzoxazole‐5‐yl)benzamide derivatives as selective COX‐2 inhibitors and anti‐inflammatory agents

A series of N‐(2‐(3,5‐dimethoxyphenyl)benzoxazole‐5‐yl)benzamide derivatives ( 3am ) was synthesized and evaluated for their in vitro inhibitory activity against COX‐1 and COX‐2. The compounds with considerable in vitro activity (IC₅₀ < 1 μM) were evaluated in vivo for their anti‐inflammatory potential by the carrageenan‐induced rat paw edema method. Out of 13 newly synthesized compounds, 3a , 3b , 3d , 3g , 3j , and 3k were found to be the most potent COX‐2 inhibitors in the in vitro enzymatic assay, with IC₅₀ values in the range of 0.06–0.71 μM. The in vivo anti‐inflammatory activity of these six compounds ( 3a , 3b , 3d , 3g , 3j , and 3k ) was assessed by the carrageenan‐induced rat paw edema method. Compounds 3d (84.09%), 3g (79.54%), and 3a (70.45%) demonstrated significant anti‐inflammatory activity compared to the standard drug ibuprofen (65.90%) and were also found to be safer than ibuprofen, by ulcerogenic studies. A docking study was done using the crystal structure of human COX‐2, to understand the binding mechanism of these inhibitors to the active site of COX‐2.

     

3‐(3‐Ethylphenyl)‐2‐substituted hydrazino‐3H‐quinazolin‐4‐one Derivatives: New Class of Analgesic and Anti‐Inflammatory Agents

A new series of 3‐(3‐ethylphenyl)‐2‐substituted hydrazino‐3H‐quinazolin‐4‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one with a variety of aldehydes and ketones. The title compounds were investigated for analgesic, anti‐inflammatory and ulcerogenic index behavior. The compound 2‐(N′‐3‐pentylidene‐hydrazino)‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one ( AS2 ) emerged as the most active compound in exhibiting analgesic activity and the compound 2‐(N′‐2‐pentylidene‐hydrazino)‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one ( AS3 ) emerged as the most active compound in exhibiting anti‐inflammatory activity; and these compounds are moderately potent when compared with the reference standard diclofenac sodium. Interestingly, the test compounds showed only mild ulcerogenic potential when compared with aspirin.     

Scalable synthesis and antibacterial evaluation of 2‐(3‐(N‐(substituted phenyl)sulfamoyl)ureido)benzothiazoles

A new series of 2‐(3‐(N‐(substituted phenyl)sulfamoyl)ureido)benzothiazoles was synthesized via a one‐pot efficient and scalable method, involving the condensation of 2‐aminobenzothiazoles derivatives, substituted anilines, and chlorosulfonyl isocyanate. The products were obtained in good yield with a simple workup, and their structures were confirmed from their spectral analyses. The synthesized compounds were further screened for their antibacterial activity against Gram‐positive and Gram‐negative pathogenic strains. The molecules show promising activity in the MIC value range of 2–0.25 µg/ml against selected bacterial strains, especially against nonfermentative carbapenem‐resistant bacteria (Pseudo VIM‐2 and Acinetobacter baumanni).