Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections

0566362 - ÚVGZ 2023 RIV CH eng J - Journal Article
Strharsky, T. - Pindjakova, D. - Kos, J. - Vrablova, L. - Smak, P. - Michnová, H. - Gonec, T. - Hošek, J. - Oravec, Michal - Jendrzejewska, I. - Čížek, A. - Jampílek, J.
Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections.
International Journal of Molecular Sciences. Roč. 23, č. 23 (2022), č. článku 15090. E-ISSN 1422-0067
R&D Projects: GA MŠMT(CZ) LM2018123; GA MŠMT(CZ) EF16_019/0000797
Institutional support: RVO:86652079
Keywords : cinnamamides * Michael acceptors * antimicrobial activity * cytotoxicity * lipophilicity * structure-activity relationships * docking study
OECD category: Biochemistry and molecular biology
Impact factor: 5.6, year: 2022
Method of publishing: Open access
https://www.mdpi.com/1422-0067/23/23/15090

A series of thirty-two anilides of 3-(trifluoromethyl)cinnamic acid (series 1) and 4-(trifluoromethyl)cinnamic acid (series 2) was prepared by microwave-assisted synthesis. All the compounds were tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). All the compounds were evaluated in vitro against Mycobacterium smegmatis ATCC 700084 and M. marinum CAMP 5644. (2E)-3-[3-(Trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]prop-2-enamide (1j), (2E)-N-(3,5-dichlorophenyl)-3-[3-(trifluoromethyl)phenyl]prop-2-enamide (1o) and (2E)-N-[3-(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)-phenyl]prop-2-enamide (2i), (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]-prop-2-enamide (2p) showed antistaphylococcal (MICs/MBCs 0.15-5.57 mu M) as well as anti-enterococcal (MICs/MBCs 2.34-44.5 mu M) activity. The growth of M. marinum was strongly inhibited by compounds 1j and 2p in a MIC range from 0.29 to 2.34 mu M, while all the agents of series 1 showed activity against M. smegnatis (MICs ranged from 9.36 to 51.7 mu M). The performed docking study demonstrated the ability of the compounds to bind to the active site of the mycobacterial enzyme InhA. The compounds had a significant effect on the inhibition of bacterial respiration, as demonstrated by the MTT assay. The compounds showed not only bacteriostatic activity but also bactericidal activity. Preliminary in vitro cytotoxicity screening was assessed using the human monocytic leukemia cell line THP-1 and, except for compound 2p, all effective agents did show insignificant cytotoxic effect. Compound 2p is an interesting anti-invasive agent with dual (cytotoxic and antibacterial) activity, while compounds 1j and 1o are the most interesting purely antibacterial compounds within the prepared molecules.
Permanent Link: https://hdl.handle.net/11104/0337705