Novel diphenyl ether-heterocycles hybrids: Synthesis via Hantzsch and Biginelli reactions, molecular docking simulation, and antimicrobial activities

Abstract

By reacting the potassium salt produced by treating 4-hydroxybenzaldehyde with ethanolic KOH with 4-fluorobenzaldehyde in DMF at reflux, 4,4′-oxydibenzaldehyde was produced. The Hantzsch reaction of 4,4′-oxydibenzaldehyde with the respective 3-aminocrotononitrile or a mixture of 1,3-dicarbonyl compounds and amine source yielded novel bis-1,4-dihydropyridin-3,5-dicarbonitrile, bis-hexahydroacridine-1,8-dione, and bis-decahydropyrimido[4,5-b]quinoline. Bis-hexahydrobenzo[4,5]imidazo[2,1-b]quinazoline and bis(tetrahydro[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one) were obtained via Biginelli-like reaction of 4,4′-oxydibenzaldehyde with both dimedone and 4H-1,2,4-triazol-3-amine or 1H-benzo[d]imidazol-2-amine, respectively. By reacting 2,2′-((oxybis(4,1-phenylene))bis(methanylylidene))bis(hydrazinecarbothioamide) with the appropriate 2-bromoacetyl derivative or α-keto-hydrazonoyl chloride in ethanol containing TEA, novel bis-thiazoles with diphenyl ether cores were successfully obtained. Antibacterial activity against several bacterial strains was investigated for all of the produced compounds. Compound 13b demonstrated good antibacterial activity against B. subtilis. A molecular docking study was done against gram-positive thymidylate kinase and bacterial DNA gyrase B to determine the mechanism of action of the active compounds.