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Development, synthesis, and biological evaluation of sulfonyl‐α‐ l ‐amino acids as potential anti‐ Helicobacter pylori and IMPDH inhibitors
Author(s) -
Galal Alaaeldin M. F.,
Mohamed Hanaa S.,
AbdelAziz Marwa M.,
Hanna Atef G.
Publication year - 2021
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.202000385
Subject(s) - chemistry , clarithromycin , helicobacter pylori , stereochemistry , docking (animal) , enzyme , minimum inhibitory concentration , biochemistry , ic50 , in vitro , antibiotics , biology , nursing , medicine , genetics
Inosine 5ʹ‐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‐α‐ 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 1 H and 13 C 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 µM, which were selected to test their inhibitory activities against Hp IMPDH 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 Hp IMPDH enzyme, with IC 50 = 2.42 and 2.56 µM, respectively. Moreover, the four compounds were found to be less active and safer against h IMPDH2 than the reference drugs, with IC 50 > 17.17 µM, which makes sure that their selectivity is toward Hp IMPDH 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 µg/ml. The molecular docking study and ADMET analysis of the most active compounds were used to elucidate the mode‐of‐action mechanism.