Consensus-Based Pharmacophore Mapping for New Set of <i>N</i>-(disubstituted-phenyl)-3-hydroxyl-naphthalene-2-carboxamides

• Main Authors: Andrzej Bak, Jiri Kos, Hana Michnova, Tomas Gonec, Sarka Pospisilova, Violetta Kozik, Alois Cizek, Adam Smolinski, Josef Jampilek
• Format: Article
• Language: English
• Published: MDPI AG 2020-09-01
• Series: International Journal of Molecular Sciences
• Subjects: hydroxynaphthalenecarboxamides; lipophilicity; antistaphylococcal activity; antitubercular activity; MIC; MTT assay
• Online Access: https://www.mdpi.com/1422-0067/21/18/6583
• ISSN: 1661-6596; 1422-0067

A series of twenty-two novel <i>N</i>-(disubstituted-phenyl)-3-hydroxynaphthalene- 2-carboxamide derivatives was synthesized and characterized as potential antimicrobial agents. <i>N</i>-[3,5-bis(trifluoromethyl)phenyl]- and <i>N</i>-[2-chloro-5-(trifluoromethyl)phenyl]-3-hydroxy- naphthalene-2-carboxamide showed submicromolar (MICs 0.16–0.68 µM) activity against methicillin-resistant <i>Staphylococcus aureus</i> isolates. <i>N</i>-[3,5-bis(trifluoromethyl)phenyl]- and <i>N</i>-[4-bromo-3-(trifluoromethyl)phenyl]-3-hydroxynaphthalene-2-carboxamide revealed activity against <i>M. tuberculosis</i> (both MICs 10 µM) comparable with that of rifampicin. Synergistic activity was observed for the combinations of ciprofloxacin with <i>N</i>-[4-bromo-3-(trifluoromethyl)phenyl]- and <i>N</i>-(4-bromo-3-fluorophenyl)-3-hydroxynaphthalene-2-carboxamides against MRSA SA 630 isolate. The similarity-related property space assessment for the congeneric series of structurally related carboxamide derivatives was performed using the principal component analysis. Interestingly, different distribution of mono-halogenated carboxamide derivatives with the –CF₃ substituent is accompanied by the increased activity profile. A symmetric matrix of Tanimoto coefficients indicated the structural dissimilarities of dichloro- and dimetoxy-substituted isomers from the remaining ones. Moreover, the quantitative sampling of similarity-related activity landscape provided a subtle picture of favorable and disallowed structural modifications that are valid for determining activity cliffs. Finally, the advanced method of neural network quantitative SAR was engaged to illustrate the key 3D steric/electronic/lipophilic features of the ligand-site composition by the systematic probing of the functional group.