Abstract
Three series of N-(pyrazin-2-yl)benzamides were designed as retro-amide analogues of previously published N-phenylpyrazine-2-carboxamides with in vitro antimycobacterial activity. The synthesized retro-amides were evaluated for in vitro growth inhibiting activity against Mycobacterium tuberculosis H37Rv (Mtb), three non-tuberculous mycobacterial strains (M. avium, M. kansasii, M. smegmatis) and selected bacterial and fungal strains of clinical importance. Regarding activity against Mtb, most N-pyrazinylbenzamides (retro-amides) possessed lower or no activity compared to the corresponding N-phenylpyrazine-2-carboxamides with the same substitution pattern. However, the active retro-amides tended to have lower HepG2 cytotoxicity and better selectivity. Derivatives with 5-chloro substitution on the pyrazine ring were generally more active compared to their 6-cloro positional isomers or non-chlorinated analogues. The best antimycobacterial activity against Mtb was found in N-(5-chloropyrazin-2-yl)benzamides with short alkyl (2h: R2 = Me; 2i: R2 = Et) in position 4 of the benzene ring (MIC = 6.25 and 3.13 µg/mL, respectively, with SI > 10). N-(5-Chloropyrazin-2-yl)benzamides with hydroxy substitution (2b: R2 = 2-OH; 2d: R2 = 4-OH) on the benzene ring or their acetylated synthetic precursors possessed the broadest spectrum of activity, being active in all three groups of mycobacterial, bacterial and fungal strains. The substantial differences in in silico calculated properties (hydrogen-bond pattern analysis, molecular electrostatic potential, HOMO and LUMO) can justify the differences in biological activities between N-pyrazinylbenzamides and N-phenylpyrazine-2-carboxamides.
Highlights
According to the latest Global Tuberculosis Report published by the WHO [1], an estimated10.4 million people worldwide developed active tuberculosis (TB) in 2016 and TB caused 1.7 million deaths, including 0.4 million deaths among HIV-positive people
The most active derivatives in all series 1, 2 and 3 follow the substitution pattern that was proposed for N-phenylpyrazine-2-carboxamides [19], that is, the benzene ring substituted with electron-withdrawing substituent in position 3 and/or electron-donating substituent in position 4
As we showed in the previous section, it is obvious that exchange of an amide linker for a retro-amide linker has profound effects on the biological activity of the pyrazine-linker-benzene-like compounds
Summary
According to the latest Global Tuberculosis Report published by the WHO [1], an estimated. Best compounds possessed tuberculosis H37Rv. in class possessed activity with MIC at micromolar level (2–20 μ M). Direct inspiration for compounds in this paper previous of 5-chloro-N-phenylpyrazine-2-carboxamides [18], which [18], werewhich generally more active was our series previous series of 5-chloro-N-phenylpyrazine-2-carboxamides were generally (best compounds with at low micromolar level) than previously studied. The benzene more active (best compounds with MIC at low micromolar level) than previously studied 6-Cl ring in the series tolerated substituents, electron-donating and electron-withdrawing, isomers. N-(pyrazin-2-yl)benzamides, which can be regarded phenylpyrazine-2-carboxamides as antimycobacterial agents, we designed a series of N-(pyrazin-2retro-amide analogues The retro-amides of PEER classical β-lactam antibiotics and their analogues were studied as substrates and/or inhibitors of beta-lactamases [21,22,23,24].
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