Synthesis, Antifungal Evaluation and In Silico Study of N-(4-Halobenzyl)amides

• Published in: Molecules (Basel, Switzerland) Vol. 21; no. 12; p. 1716
• Main Authors: Montes, Ricardo Carneiro, Perez, Ana Luiza A L, Medeiros, Cássio Ilan S, Araújo, Marianna Oliveira de, Lima, Edeltrudes de Oliveira, Scotti, Marcus Tullius, Sousa, Damião Pergentino de
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13.12.2016; MDPI
• Subjects: Acids; Amides - chemical synthesis; Amides - pharmacology; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; antimicrobial activity; Antimicrobial agents; Biological activity; Candida; Candida - drug effects; Candida albicans; Candida krusei; Candida tropicalis; Carbon-13 Magnetic Resonance Spectroscopy; Computer Simulation; halogenated amides; Hydrogen bonds; Mass Spectrometry; Microbial Sensitivity Tests; NMR; Nuclear magnetic resonance; Proton Magnetic Resonance Spectroscopy; Quantitative Structure-Activity Relationship; vanillic acid derivatives; Brazil; antimicrobial activity; vanillic acid derivatives; halogenated amides; Candida
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules21121716

A collection of 32 structurally related -(4-halobenzyl)amides were synthesized from cinnamic and benzoic acids through coupling reactions with 4-halobenzylamines, using (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) as a coupling agent. The compounds were identified by spectroscopic methods such as infrared, ¹H- and C- Nuclear Magnetic Resonance (NMR) and high-resolution mass spectrometry. The compounds were then submitted to antimicrobial tests by the minimum inhibitory concentration method (MIC) and nystatin was used as a control in the antifungal assays. The purpose of the tests was to evaluate the influence of structural changes in the cinnamic and benzoic acid substructures on the inhibitory activity against strains of , , and . A quantitative structure-activity relationship (QSAR) study with KNIME v. 3.1.0 and Volsurf v. 1.0.7 softwares were realized, showing that descriptors DRDRDR, DRDRAC, L4LgS, IW4 and DD2 influence the antifungal activity of the haloamides. In general, 10 benzamides revealed fungal sensitivity, especially a vanillic amide which enjoyed the lowest MIC. The results demonstrate that a hydroxyl group in the position, and a methoxyl at the position enhance antifungal activity for the amide skeletal structure. In addition, the double bond as a spacer group appears to be important for the activity of amide structures.