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Substituted N-phenylitaconamides as inhibitors of mycobacteria and mycobacterial isocitrate lyase

M. Krátký, E. Novotná, J. Stolaříková, M. Švarcová, J. Vinšová

. 2022 ; 176 (-) : 106252. [pub] 20220703

Jazyk angličtina Země Nizozemsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc22024567

Novel antimycobacterial drugs are needed, especially those with dual activity against both actively growing and non-replicating subpopulations of mycobacteria. Isocitrate lyase (ICL) is one of proposed targets and this enzyme is inhibited by itaconic acid. That is why we have designed and prepared sixteen amides of itaconic acid and various anilines and amine antimicrobial drugs to evaluate them as potential inhibitors of ICL and antimycobacterial agents. N-Phenylitaconamides were prepared from itaconic anhydride and substituted anilines (yields 57-99%). They were characterized and evaluated against mycobacterial ICL and against actively growing mycobacteria (M. tuberculosis H37Rv, M. avium, two strains of M. kansasii). All derivatives showed antimycobacterial efficacy with minimum inhibitory concentrations starting from 125 μM. M. kansasii was the most susceptible species. Itaconamides derived from sulfonamides or p-aminosalicylic acid were optimal for activity against extracellular mycobacteria. ICL1 was significantly inhibited by two compounds, with 2-methylene-4-[(4-nitrophenyl)amino]-4-oxobutanoic acid 1k being the most potent (36% inhibition at 10 μM), which was also more efficient than two comparators. Molecular docking revealed its mode of binding to the enzyme. Using in silico tools, physicochemical properties and structural features for drug-likeness and gastrointestinal absorption were evaluated.

Citace poskytuje Crossref.org

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$a Novel antimycobacterial drugs are needed, especially those with dual activity against both actively growing and non-replicating subpopulations of mycobacteria. Isocitrate lyase (ICL) is one of proposed targets and this enzyme is inhibited by itaconic acid. That is why we have designed and prepared sixteen amides of itaconic acid and various anilines and amine antimicrobial drugs to evaluate them as potential inhibitors of ICL and antimycobacterial agents. N-Phenylitaconamides were prepared from itaconic anhydride and substituted anilines (yields 57-99%). They were characterized and evaluated against mycobacterial ICL and against actively growing mycobacteria (M. tuberculosis H37Rv, M. avium, two strains of M. kansasii). All derivatives showed antimycobacterial efficacy with minimum inhibitory concentrations starting from 125 μM. M. kansasii was the most susceptible species. Itaconamides derived from sulfonamides or p-aminosalicylic acid were optimal for activity against extracellular mycobacteria. ICL1 was significantly inhibited by two compounds, with 2-methylene-4-[(4-nitrophenyl)amino]-4-oxobutanoic acid 1k being the most potent (36% inhibition at 10 μM), which was also more efficient than two comparators. Molecular docking revealed its mode of binding to the enzyme. Using in silico tools, physicochemical properties and structural features for drug-likeness and gastrointestinal absorption were evaluated.
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$a Švarcová, Markéta $u Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czechia; Department of Chemistry, Faculty of Science, J. E. Purkinje University, Pasteurova 3632/15, 400 96 Ústí nad Labem, Czechia
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$a Vinšová, Jarmila $u Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czechia
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