Antimicrobial and ADME properties of methoxylated, methylated and nitrated 2-hydroxynaphthalene-1 carboxanilides: Original scientific article

Lucia Vrablova; Tomas Gonec; Tereza Kauerova; Michal Oravec; Izabela Jendrzejewska; Peter Kollar; Alois Cizek; Josef Jampilek

doi:10.5599/admet.2642

Authors

Lucia Vrablova Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 842 15 Bratislava, Slovakia https://orcid.org/0009-0008-4701-5265
Tomas Gonec Department of Chemical Drugs, Faculty of Pharmacy, Masaryk University, Palackeho tr. 1946/1, 612 00 Brno, Czech Republic https://orcid.org/0000-0003-3712-8641
Tereza Kauerova Department of Pharmacology and Toxicology, Faculty of Pharmacy, Masaryk University, Palackeho tr. 1946/1, 612 00 Brno, Czech Republic https://orcid.org/0000-0003-2854-511X
Michal Oravec Global Change Research Institute CAS, Belidla 986/4a, 603 00 Brno, Czech Republic https://orcid.org/0000-0002-2506-5826
Izabela Jendrzejewska Institute of Chemistry, University of Silesia, Bankowa 12, 40007 Katowice, Poland https://orcid.org/0000-0002-6025-5772
Peter Kollar Department of Pharmacology and Toxicology, Faculty of Pharmacy, Masaryk University, Palackeho tr. 1946/1, 612 00 Brno, Czech Republic https://orcid.org/0000-0003-2265-1528
Alois Cizek Department of Infectious Diseases and Microbiology, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Palackeho tr. 1946/1, 612 42 Brno, Czech Republic https://orcid.org/0000-0001-5706-4601
Josef Jampilek Department of Chemical Biology, Faculty of Science, Palacky University Olomouc, Slechtitelu 27, 779 00 Olomouc, Czech Republic https://orcid.org/0000-0003-2003-9052

DOI:

https://doi.org/10.5599/admet.2642

Keywords:

Lipophilicity, antibacterial activity, antimycobacterial activity, cytotoxicity

Abstract

Background and purpose: Many new compounds are being prepared to overcome the problem of increasing microbial resistance and the increasing number of infections. Experimental approach: This study includes a series of twenty-seven mono-, di- and trisubstituted 2-hydroxynaphthalene-1-carboxanilides designed as multitarget agents. The compounds are substituted with methoxy, methyl, and nitro groups, as well as additionally with chlorine, bromine, and trifluoromethyl at various positions. All the compounds were evaluated for antibacterial activities against Gram-positive and Gram-negative bacteria and mycobacteria. Cytotoxicity on human cells was also tested. Key results: Three compounds showed activity comparable to clinically used drugs. N-(3,5-Dimethylphenyl)-2-hydroxynaphthalene-1-carboxamide (13) showed only anti¬sta¬phylococcal activity (minimum inhibitory concentration (MIC) = 54.9 µM); 2-hydroxy-N-[2-methyl-5-(tri¬fluoro¬methyl)phenyl]naphthalene-1-carboxamide (22) and 2-hydroxy-N-[4-nitro-3-(trifluoromethyl)phe¬nyl]na¬phtha¬lene-1-carboxamide (27) were active across the entire spectrum of tested bacteria/mycobacteria, both against the sensitive set and against resistant isolates (MICs range 0.3 to 92.6 µM). Compound 22 was even active against E. coli (MIC = 23.2 µM). The active agents showed no in vitro cytotoxicity up to a concentration of 30 μM. Conclusion: Compounds with trifluoromethyl in the meta-anilide position, experimental lipophilicity expressed as log k (logarithm of the capacity factor) in the range of 0.31 to 0.34 and calculated electron σ parameter for the anilide substituent higher than 0.59 were effective. The investigated compounds meet the definition of Michael acceptors. Based on ADME screening, the investigated compounds 13, 22 and 27 should have suitable physico¬chemical parameters for good bioavailability in the organism. Therefore, these are promising agents for further study.

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