Trifluoromethylcinnamanilides - Effective dual inhibitors of Mycobacterium smegmatis and Plasmodium falciparum.

Autor: Kos J; Department of Biochemistry, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. Electronic address: jirikos85@gmail.com., Strharsky T; Department of Chemical Drugs, Faculty of Pharmacy, Masaryk University, Palackeho 1946/1, 612 00 Brno, Czech Republic. Electronic address: strharsky.t@gmail.com., Tosso R; Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis, IMIBIO-CONICET, Ejército de los Andes 950, 5700 San Luis, Argentina. Electronic address: rodri.tosso@gmail.com., Gutierrez L; Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis, IMIBIO-CONICET, Ejército de los Andes 950, 5700 San Luis, Argentina. Electronic address: lucasgutierrez10@gmail.com., Kos D; Department of Molecular Pharmacy, Faculty of Pharmacy, Masaryk University, Palackeho 1946/1, 612 00 Brno, Czech Republic. Electronic address: kosd@pharm.muni.cz., Jurica J; Department of Pharmacology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. Electronic address: jurica@med.muni.cz., Zendulka O; Department of Pharmacology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. Electronic address: zendulka@med.muni.cz., Pes O; Department of Biochemistry, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. Electronic address: opes@med.muni.cz., Gregorova J; Department of Biochemistry, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. Electronic address: jgregorova@med.muni.cz., Degotte G; Renslo's Lab, Department of Pharmaceutical Chemistry, University California San Francisco, 600 16(th) Street, 94143 San Francisco, CA, USA. Electronic address: dgilles@hotmail.be., Gonec T; Department of Chemical Drugs, Faculty of Pharmacy, Masaryk University, Palackeho 1946/1, 612 00 Brno, Czech Republic. Electronic address: t.gonec@seznam.cz., Oravec M; Global Change Research Institute CAS, Belidla 986/4a, 603 00 Brno, Czech Republic. Electronic address: oravec.m@czechglobe.cz., Vojackova V; Department of Experimental Biology, Faculty of Science, Palacky University Olomouc, Slechtitelu 27, 779 00 Olomouc, Czech Republic. Electronic address: veronika.vojackova@upol.cz., Krystof V; Department of Experimental Biology, Faculty of Science, Palacky University Olomouc, Slechtitelu 27, 779 00 Olomouc, Czech Republic. Electronic address: vladimir.krystof@upol.cz., Cizek A; Department of Infectious Diseases and Microbiology, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Palackeho tr. 1946/1, 612 42 Brno, Czech Republic. Electronic address: cizeka@vfu.cz., Francotte P; Laboratory of Medicinal Chemistry, CIRM - Center for Interdisciplinary Research on Medicines, University of Liege, Avenue Hippocrate 15, 4000 Liege, Belgium. Electronic address: pierre.francotte@uliege.be., Frederich M; Laboratory of Pharmacognosy, CIRM - Center for Interdisciplinary Research on Medicines, University of Liege, Avenue Hippocrate 15, 4000 Liege, Belgium. Electronic address: m.frederich@uliege.be., Jampilek J; Department of Chemical Biology, Faculty of Science, Palacky University Olomouc, Slechtitelu 27, 779 00 Olomouc, Czech Republic; Institute of Chemistry, University of Silesia, Szkolna 9, 40-007 Katowice, Poland. Electronic address: josef.jampilek@gmail.com., Enriz D; Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis, IMIBIO-CONICET, Ejército de los Andes 950, 5700 San Luis, Argentina. Electronic address: danielenriz@gmail.com.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 Nov 19; Vol. 154, pp. 107957. Date of Electronic Publication: 2024 Nov 19.
DOI: 10.1016/j.bioorg.2024.107957
Abstrakt: A series of eighteen new 2-trifluoromethylcinnamanilides (1a-r) were synthesized by microwave synthesis and investigated for their antimycobacterial and antimalarial activities, along with the complementary (2E)-3-[3-(trifluoromethyl)phenyl]-N-arylprop-2-enanilides (2a-r) and (2E)-3-[4-(trifluoromethyl)phenyl]-N-arylprop-2-enanilides (3a-r) prepared earlier. All the compounds were evaluated in vitro against Mycobacterium smegmatis ATCC 700084 and a chloroquine-sensitive strain of Plasmodium falciparum 3D7/MRA-102. The most active compounds against M. smegmatis (MIC values in the range of 1.17-11.1 µM, more effective than rifampicin) were anilides substituted by 3,5-CF 3 (1q, 2q, 3q), 4-OCF 3 (1k), and 4-CF 3 (1j, 2j). The most effective agents against P. falciparum (IC 50 values in the range of 0.32-4.5 µM, comparable to chloroquine) were anilides substituted by 3,5-CF 3 (1q, 2q, 3q), 2-Br-4-OCF 3 (1r), 4-CF 3 (1j, 3j), 4-F (2d), 4-Cl (2g), 2-Cl (1e, 2e). A preliminary in vitro cytotoxicity screening was assessed using human leukemic cell lines and human dermal fibroblasts, revealing the toxic effect of 3,5-CF 3 substituted anilides. On the other hand, the other investigated agents showed insignificant cytotoxic effects. Stability assays using rat liver microsomes demonstrated that compounds 1r (R = 2-Br-4-OCF 3 ) and 1q (R = 3,5-CF 3 ) are neither metabolized nor affect cytochrome P450 metabolizing capacity in vitro. Furthermore, complex in silico studies were performed - a combined approach (docking/MD simulations/QTAIM calculations) helped to define the molecular interactions that were applied during the binding of active agents and the subsequent inhibition of their molecular targets - InhA (activity against M. smegmatis) and arginase (activity against P. falciparum). In conclusion, promising active agents with dual antimycobacterial and antimalarial effects were identified.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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