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Title: Consensus-based pharmacophore mapping for new set of N-(disubstitutedphenyl)- 3-hydroxyl-naphthalene-2-carboxamides
Authors: Bąk, Andrzej
Kos, Jiri
Michnova, Hana
Gonec, Tomas
Pospisilova, Sarka
Kozik, Violetta
Cizek, Alois
Smoliński, Adam
Jampilek, Josef
Keywords: hydroxynaphthalenecarboxamides; lipophilicity; antistaphylococcal activity; antitubercular activity; MIC; MTT assay; CoMSA; VE-PLS; similarity-activity landscape index
Issue Date: 2020
Citation: "International Journal of Molecular Sciences" (2020) Iss. 18, art. no. 6583
Abstract: A series of twenty-two novel N-(disubstituted-phenyl)-3-hydroxynaphthalene- 2-carboxamide derivatives was synthesized and characterized as potential antimicrobial agents. N-[3,5-bis(trifluoromethyl)phenyl]- and N-[2-chloro-5-(trifluoromethyl)phenyl]-3-hydroxynaphthalene- 2-carboxamide showed submicromolar (MICs 0.16–0.68 M) activity against methicillin-resistant Staphylococcus aureus isolates. N-[3,5-bis(trifluoromethyl)phenyl]- and N-[4-bromo-3-(trifluoromethyl)phenyl]-3-hydroxynaphthalene-2-carboxamide revealed activity against M. tuberculosis (both MICs 10 M) comparable with that of rifampicin. Synergistic activity was observed for the combinations of ciprofloxacin with N-[4-bromo-3-(trifluoromethyl)phenyl]- and N-(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, di erent distribution of mono-halogenated carboxamide derivatives with the –CF3 substituent is accompanied by the increased activity profile. A symmetric matrix of Tanimoto coe cients 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 cli s. 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.
DOI: 10.3390/ijms21186583
ISSN: 1422-0067
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