Development, synthesis, and biological evaluation of sulfonyl-α-l-amino acids as potential anti-Helicobacter pylori and IMPDH inhibitors

Inosine 5MODIFIER LETTER PRIME-monophosphate dehydrogenase (IMPDH) catalyzes a crucial step in the biosynthesis of DNA and RNA, and it has been exploited as a promising target for antimicrobial therapy. The present study discusses the development and synthesis of a series of sulfonyl-alpha-l-amino acids coupled with the anisamide scaffold and evaluates their activities as anti-Helicobacter pylori and IMPDH inhibitors. Twenty derivatives were synthesized and their structures were established by high-resolution mass spectrometry and H-1 and C-13 nuclear magnetic resonance measurements. Four compounds (6, 10, 11, and 21) were found to be the most potent and selective molecules in the series with minimum inhibitory concentration (MIC) values <17 mu M, which were selected to test their inhibitory activities against HpIMPDH and human (h)IMPDH2 enzymes. In all tests, amoxicillin and clarithromycin were used as reference drugs. Compounds 6 and 10 were found to have a promising activity against the HpIMPDH enzyme, with IC50 = 2.42 and 2.56 mu M, respectively. Moreover, the four compounds were found to be less active and safer against hIMPDH2 than the reference drugs, with IC50 > 17.17 mu M, which makes sure that their selectivity is toward HpIMPDH and reverse to that of amoxicillin and clarithromycin. Also, the synergistic antibacterial activity of compounds 6, 10, amoxicillin, and clarithromycin was investigated in vitro. The combination of amoxicillin/compound 6 (2:1 by weight) exhibited a significant antibacterial activity against H. pylori, with MIC = 0.12 mu g/ml. The molecular docking study and ADMET analysis of the most active compounds were used to elucidate the mode-of-action mechanism.

Automated summary

This study focused on the development and synthesis of sulfonyl-alpha-l-amino acids coupled with the anisamide scaffold for their anti-Helicobacter pylori and IMPDH inhibitory activities. Among the synthesized derivatives, compounds 6 and 10 exhibited promising inhibitory activities against the HpIMPDH enzyme, with IC50 values of 2.42 and 2.56 µM, respectively. Additionally, the compounds showed less activity and higher safety against hIMPDH2 compared to the reference drugs, indicating a potential selectivity towards HpIMPDH.