Trifluoromethylcinnamanilides - Effective dual inhibitors of Mycobacterium smegmatis and Plasmodium falciparum
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
39615279
DOI
10.1016/j.bioorg.2024.107957
PII: S0045-2068(24)00862-9
Knihovny.cz E-resources
- Keywords
- Cinnamanilides, Cytotoxicity, Lipophilicity, M. smegmatis, Molecular modeling, P. falciparum, QTAIM calculations,
- MeSH
- Anilides pharmacology chemistry chemical synthesis MeSH
- Anti-Bacterial Agents pharmacology chemistry chemical synthesis MeSH
- Antimalarials * pharmacology chemistry chemical synthesis MeSH
- Rats MeSH
- Humans MeSH
- Microbial Sensitivity Tests MeSH
- Molecular Structure MeSH
- Mycobacterium smegmatis * drug effects MeSH
- Parasitic Sensitivity Tests MeSH
- Plasmodium falciparum * drug effects MeSH
- Molecular Docking Simulation MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Anilides MeSH
- Anti-Bacterial Agents MeSH
- Antimalarials * MeSH
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-CF3 (1q, 2q, 3q), 4-OCF3 (1k), and 4-CF3 (1j, 2j). The most effective agents against P. falciparum (IC50 values in the range of 0.32-4.5 µM, comparable to chloroquine) were anilides substituted by 3,5-CF3 (1q, 2q, 3q), 2-Br-4-OCF3 (1r), 4-CF3 (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-CF3 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-OCF3) and 1q (R = 3,5-CF3) 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.
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