Scaffold morphing leading to evolution of 2,4-diaminoquinolines and aminopyrazolopyrimidines as inhibitors of the ATP synthesis pathway
| Autor: | Manoranjan Panda, Anandkumar Raichurkar, Neela Dinesh, Vinayak Hosagrahara, Naveen Kumar, K.R. Prabhakar, Suresh Rudrapatna, Gayathri Balakrishnan, Amit K. Gupta, Vasan K. Sambandamurthy, Karthikeyan Kandaswamy, Stefan Kavanagh, Ramanatha Saralaya, Lalit kumar Jena, Shridhar Narayanan, Suresh Solapure, Robert Nanduri, V. Balasubramanian, Meenakshi Mallya, Ashwini Narayan, Sowmya Bharath, Vijender Panduga, Vikas Shinde, Jitendar Reddy, Khisi Mdluili, Christopher B. Cooper, Parvinder Kaur, Shahul Hameed P, Sreevalli Sharma, Supreeth Guptha, Kakoli Mukherjee, Sudha Ravishankar, Radha Shandil, Pravin Iyer, Shankar D. Markad, Vasanthi Ramachandran, Takahiro Yano, Jyothi Bhat, Harvey Rubin, Subramanyam J. Tantry |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pharmacology chemistry.chemical_classification Scaffold ATP synthase 030106 microbiology Organic Chemistry Assay Pharmaceutical Science Biology biology.organism_classification Biochemistry Pyrazolopyrimidine Mycobacterium tuberculosis 03 medical and health sciences chemistry.chemical_compound Enzyme chemistry Drug Discovery Quinazoline biology.protein Molecular Medicine Bedaquiline |
| Zdroj: | MedChemComm. 7:1022-1032 |
| ISSN: | 2040-2511 2040-2503 |
| Popis: | The success of bedaquiline as an anti-tubercular agent for the treatment of multidrug-resistant tuberculosis has validated the ATP synthesis pathway and in particular ATP synthase as an attractive target. However, limitations associated with its use in the clinic and the drug–drug interactions with rifampicin have prompted research efforts towards identifying alternative ATP synthesis inhibitors with differentiated mechanisms of action. A biochemical assay was employed to screen AstraZeneca's corporate compound collection to identify the inhibitors of mycobacterial ATP synthesis. The high-throughput screening resulted in the identification of 2,4-diaminoquinazolines as inhibitors of the ATP synthesis pathway. A structure–activity relationship for the quinazolines was established and the knowledge was utilized to morph the quinazoline core into quinoline and pyrazolopyrimidine to expand the scope of chemical diversity. The morphed scaffolds exhibited a 10-fold improvement in enzyme potency and over 100-fold improvement in selectivity against inhibition of mammalian mitochondrial ATP synthesis. These novel compounds were bactericidal and demonstrated growth retardation of Mycobacterium tuberculosis in the acute mouse model of tuberculosis infection. |
| Databáze: | OpenAIRE |
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