Design and Development of New Benzopyrazole Derivatives as Selective Inhibitors of Helicobacter pylori IMPDH

Beznopyrazole based molecules are investigated as potential H. pylori IMPDH inhibitors. A total of 36 molecules having 3-carboxamido and 1-acetamido linker are designed and synthesized. Compounds SN-8.1 and SN-8.2 are the most potent HpIMPDH inhibitors with inhibitory concentrations in nanomolar range. All the investigated molecules are selective over host IMPDH2 and are non-toxic to fibroblast cells.

Abstract

Helicobacter pylori (H. pylori) is a Gram-negative bacterial pathogen responsible for gastritis, peptic ulcers, and gastric cancer. Current treatment regimens involve triple or quadruple antibiotic therapies; however, the rise in antibiotic resistance necessitates the development of alternative therapeutic strategies. This study explores the potential of targeting H. pylori inosine-5-monophosphate dehydrogenase (HpIMPDH), a crucial enzyme in purine nucleotide biosynthesis essential for bacterial proliferation. A novel series of benzopyrazole derivatives was designed and synthesized as potential HpIMPDH inhibitors. Biochemical assays revealed that the synthesized compounds exhibited potent inhibitory activity, with SN-8.1 and SN-8.2 displaying IC₅₀ values of 0.122 and 0.187 µM, respectively. These compounds showed minimal inhibition of human IMPDH2, suggesting selectivity toward the bacterial enzyme. Molecular docking studies further confirmed strong binding affinities at the HpIMPDH active site. Cytotoxicity assays indicated that the compounds were nontoxic at the tested concentrations. These findings demonstrate that benzopyrazole-based HpIMPDH inhibitors offer a promising strategy for the development of new anti-H. pylori agents.

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