Novel acyl thiourea derivatives: Synthesis, antifungal activity, gene toxicity, drug‐like and molecular docking screening

• Published in: Archiv der Pharmazie (Weinheim) Vol. 352; no. 2; pp. e1800275 - n/a
• Main Authors: Antypenko, Lyudmyla, Meyer, Fatuma, Kholodniak, Olena, Sadykova, Zhanar, Jirásková, Tereza, Troianova, Anastasiia, Buhaiova, Vladlena, Cao, Surui, Kovalenko, Sergiy, Garbe, Leif‐Alexander, Steffens, Karl G.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.02.2019; Wiley Subscription Services, Inc
• Subjects: Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; anti‐phytopathogens; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Chromatography, Liquid - methods; drug likeness; gene toxicity; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Mass Spectrometry - methods; molecular docking; Molecular Docking Simulation; Mutagenicity Tests; N‐(2‐carbamothioylhydrazine‐1‐carbonothioyl)cyclopropanecarboxamide; N‐substituted N‐(hydrazinecarbonothioyl)‐cyclopropanecarbox(benz)amides; Pharmacology & Pharmacy; Physical Sciences; Salmonella - drug effects; Salmonella - genetics; Science & Technology; Structure-Activity Relationship; Thiourea - analogs & derivatives; Thiourea - chemical synthesis; Thiourea - pharmacology; N-substituted N-(hydrazinecarbonothioyl)-cyclopropanecarbox(benz)amides; gene toxicity; molecular docking; N-(2-carbamothioylhydrazine-1-carbonothioyl)cyclopropanecarboxamide; anti-phytopathogens; REACTIVITY; drug likeness; MUTAGENICITY
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201800275

Nine novel acyl thioureas were synthesized. Their identities and purities were confirmed by LC‐MS spectra; each structure was elucidated by elemental analysis, IR, 1Н and 13C NMR spectra. Applying an in vitro screening of their antifungal potential, three substances (3, 5, and 6) could be selected as showing high activity against 11 fungi and 3 Phytophthora strains of phytopathogenic significance. Analysis of gene toxicity with the Salmonella reverse mutagenicity test, as an assessment of drug likeness, lipophilicity, and calculations of frontier molecular orbitals assign a low toxicity profile to these compounds. Molecular docking studies point to 14α‐demethylase (CYP51) and N‐myristoyltransferase (NMT) as possible fungal targets for growth inhibition. The findings are discussed with respect to structure–activity relationship (SAR). In an in vitro antifungal screening of nine novel acyl thioureas, three (3, 5, and 6) show high activity against 11 fungi and 3 oomycete strains of phytopathogenic significance. Analysis of gene toxicity, drug likeness, and calculations of frontier molecular orbitals demonstrate their low toxicity profile. Molecular docking studies point to 14α‐demethylase and N‐myristoyltransferase as possible antifungal targets.