Structure based de novo design of IspD inhibitors as anti-tubercular agents

Abstract

Abstract:Tuberculosis is one of the leading contagious diseases, caused by Mycobacterium tuberculosis. Despite improvements in anti-tubercular agents, it remains one of the most prevalent infectious diseases worldwide, responsible for a total of 1.6 million deaths annually. The emergence of multidrug resistant strains highlighted the need of discovering novel drug targets for the development of anti-tubercular agents. 2-C-methyl-D-erythritol-4-phosphate cytidyltransferase (IspD) is an enzyme involved in MEP pathway for isoprenoid biosynthesis, which is considered as an attractive target for the discovery of novel antibiotics for its essentiality in bacteria and absence in mammals. In the present study, we have employed structure based drug design approach to develop novel and potent inhibitors for IspD receptor. To explore binding affinity and hydrogen bond interaction between the ligand and active site of IspD receptor, docking studies were performed. ADMET and synthetic accessibility filters were used to screen designed molecules. Finally, ten compounds were selected and subsequently submitted for the synthesis and in vitro studies as IspD inhibitors.

Development of Inhibitors of the 2C-Methyl-d-erythritol 4-Phosphate (MEP) Pathway Enzymes as Potential Anti-Infective Agents

“…The compounds were selected based on their ADMET properties and synthetic accessibility using different software, but their in vitro activity against M. tuberculosis IspD has yet to be tested. 123 Domiphen bromide (DMB, 60) was identified by a HTS approach and inhibits M. smegmatis IspD with an IC 50 of 33 μg/ mL (Chart 5). 124 Besides its activity against IspD, DMB was found to inhibit the growth of M. smegmatis also by affecting IspD-independent pathways and in addition, it displays comparable MIC values with respect to isoniazide and rifampicin against MDR and XDR strains of tuberculosis.…”

“…A series of virtual hits, designed so as to occupy the active site of M. tuberculosis IspD, has been reported by Varikoti et al bearing a central aminopyrimidine scaffold decorated with different substituents at the 2 and 6 positions of the pyrimidine ring and at the amino group (e.g., 59 , Chart ). The compounds were selected based on their ADMET properties and synthetic accessibility using different software, but their in vitro activity against M. tuberculosis IspD has yet to be tested …”