| Summary: | <i>Helicobacter pylori</i> (<i>H. pylori</i>) is a pathogen that can remain in the stomach of an infected person for their entire life. As a result, this leads to the development of severe gastric diseases such as gastric cancer. In addition, current therapies have several problems including antibiotics resistance. Therefore, new practical options to eliminate this bacterium, and its induced affections, are required to avoid morbidity and mortality worldwide. One strategy in the search for new drugs is to detect compounds that inhibit a limiting step in a central metabolic pathway of the pathogen of interest. In this work, we tested 55 compounds to gain insights into their possible use as new inhibitory drugs of <i>H. pylori</i> glucose-6-phosphate dehydrogenase (HpG6PD) activity. The compounds <b>YGC-1</b>; <b>MGD-1, MGD-2; TDA-1</b>; and <b>JMM-3</b> with their respective scaffold 1,3-thiazolidine-2,4-dione; <i>1H</i>-benzimidazole; 1,3-benzoxazole, morpholine, and biphenylcarbonitrile showed the best inhibitory activity (IC<sub>50</sub> = 310, 465, 340, 204 and 304 μM, respectively). We then modeled the HpG6PD protein by homology modeling to conduct an in silico study of the chemical compounds and discovers its possible interactions with the HpG6PD enzyme. We found that compounds can be internalized at the NADP<sup>+</sup> catalytic binding site. Hence, they probably exert a competitive inhibitory effect with NADP<sup>+</sup> and a non-competitive or uncompetitive effect with G6P, that of the compounds binding far from the enzyme’s active site. Based on these findings, the tested compounds inhibiting HpG6PD represent promising novel drug candidates against <i>H. pylori</i>.
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