Scaffold Morphing To Identify Novel DprE1 Inhibitors with Antimycobacterial Activity
| Autor: | Vijender Panduga, Manoranjan Panda, Radha Shandil, Shridhar Narayanan, Naveen Kumar, M Sreenivasaiah, Monalisa Chatterji, Pravin S. Shirude, Claire Sadler, Vasan K. Sambandamurthy, Tommasi Ruben A, Supreeth Guptha, Jyothi Mahadevaswamy, Meenakshi Mallya, Pravin Iyer, Sreevalli Sharma, Vasanthi Ramachandran, Christopher B. Cooper, Anisha Ambady, Ashwini Narayan, Manjunatha M R, Khisi Mdluli, Scott Butler |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
chemistry.chemical_classification
Benzimidazole Scaffold Molecular model biology 010405 organic chemistry medicine.drug_class Organic Chemistry Active site Antimycobacterial biology.organism_classification 01 natural sciences Biochemistry Combinatorial chemistry 0104 chemical sciences Mycobacterium tuberculosis 010404 medicinal & biomolecular chemistry chemistry.chemical_compound Enzyme chemistry Drug Discovery medicine biology.protein Clinical progression |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] We report a novel benzimidazole (BI) based DprE1 inhibitor that resulted from scaffold morphing of a 1,4-azaindole series. The clinical progression of the 1,4-azaindole series from our previous work validates the potential of exploring newer chemical entities with antimycobacterial activity driven via a noncovalent inhibition of the decaprenylphosphoryl-β-d-ribose-2′-epimerase (DprE1). The representative compounds from the new scaffold reported in this study exhibited an improved solubility and higher free plasma fraction, while retaining potent DprE1 inhibition and antimycobacterial activity. A representative compound from the benzimidazole series demonstrated good efficacy in a murine model of tuberculosis. Furthermore, molecular modeling of the BI scaffold suggests plausible modes of binding in the active site of DprE1 enzyme from Mycobacterium tuberculosis that can be used for further exploration of the series. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|