RESUMO
BACKGROUND & OBJECTIVE: Helicobacter pylori infection is one of the primary causes of peptic ulcer followed by gastric cancer in the world population. Due to increased occurrences of multi-drug resistance to the currently available antibiotics, there is an urgent need for a new class of drugs against H. pylori. Inosine 5'-monophosphate dehydrogenase (IMPDH), a metabolic enzyme plays a significant role in cell proliferation and cell growth. It catalyses guanine nucleotide synthesis. IMPDH enzyme has been exploited as a target for antiviral, anticancer and immunosuppressive drugs. Recently, bacterial IMPDH has been studied as a potential target for treating bacterial infections. Differences in the structural and kinetic parameters of the eukaryotic and prokaryotic IMPDH make it possible to target bacterial enzyme selectively. METHODS: In the current work, we have synthesised and studied the effect of substituted 3-aryldiazenyl indoles on Helicobacter pylori IMPDH (HpIMPDH) activity. The synthesised molecules were examined for their inhibitory potential against recombinant HpIMPDH. RESULTS: In this study, compounds 1 and 2 were found to be the most potent inhibitors amongst the database with IC50 of 0.8 ± 0.02µM and 1 ± 0.03 µM, respectively. CONCLUSION: When compared to the most potent known HpIMPDH inhibitor molecule C91, 1 was only four-fold less potent and can be a good lead for further development of selective and potent inhibitors of HpIMPDH.
Assuntos
Inibidores Enzimáticos/farmacologia , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/enzimologia , IMP Desidrogenase/antagonistas & inibidores , Indóis/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , IMP Desidrogenase/metabolismo , Indóis/síntese química , Indóis/química , Estrutura Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
The first α-alkylation of α,ß,γ,δ-unsaturated aldehydes is achieved under mild reaction conditions. Several α,ß,γ,δ-unsaturated aldehydes and diarylcarbinols are successfully tested for the synthesis of MBH-type α-alkylated products with an excellent regioselectivity. Simple pyrrolidine is efficiently used as a catalyst to achieve a perfect E/Z selectivity of the α-alkylated products.