Scaffold morphing leading to evolution of 2,4-diaminoquinolines and aminopyrazolopyrimidines as inhibitors of the ATP synthesis pathway

Subramanyam J. Tantry; Vikas Shinde; Gayathri Balakrishnan; Shankar D. Markad; Amit K. Gupta; Jyothi Bhat; Ashwini Narayan; Anandkumar Raichurkar; Lalit Kumar Jena; Sreevalli Sharma; Naveen Kumar; Robert Nanduri; Sowmya Bharath; Jitendar Reddy; Vijender Panduga; K. R. Prabhakar; Karthikeyan Kandaswamy; Parvinder Kaur; Neela Dinesh; Supreeth Guptha; Ramanatha Saralaya; Manoranjan Panda; Suresh Rudrapatna; Meenakshi Mallya; Harvey Rubin; Takahiro Yano; Khisi Mdluili; Christopher B. Cooper; V. Balasubramanian; Vasan K. Sambandamurthy; Vasanthi Ramachandran; Radha Shandil; Stefan Kavanagh; Shridhar Narayanan; Pravin Iyer; Kakoli Mukherjee; Vinayak P. Hosagrahara; Suresh Solapure; Shahul Hameed P; Sudha Ravishankar

doi:10.1039/C5MD00589B

Scaffold morphing leading to evolution of 2,4-diaminoquinolines and aminopyrazolopyrimidines as inhibitors of the ATP synthesis pathway†‡

Subramanyam J. Tantry,^a Vikas Shinde,^a Gayathri Balakrishnan,^a Shankar D. Markad,^a Amit K. Gupta,^a Jyothi Bhat,^a Ashwini Narayan,^a Anandkumar Raichurkar,^a Lalit Kumar Jena,^a Sreevalli Sharma,^a Naveen Kumar,^a Robert Nanduri,^a Sowmya Bharath,^a Jitendar Reddy,^a Vijender Panduga,^a K. R. Prabhakar,^a Karthikeyan Kandaswamy,^a Parvinder Kaur,^a Neela Dinesh,^a Supreeth Guptha,^a Ramanatha Saralaya,^a Manoranjan Panda,^a Suresh Rudrapatna,^a Meenakshi Mallya,^a Harvey Rubin,^d Takahiro Yano,^d Khisi Mdluili,^b Christopher B. Cooper,^b V. Balasubramanian,^a Vasan K. Sambandamurthy,^a Vasanthi Ramachandran,^a Radha Shandil,^a Stefan Kavanagh,^c Shridhar Narayanan,^a Pravin Iyer,^a Kakoli Mukherjee,^a Vinayak P. Hosagrahara,^a Suresh Solapure,^a Shahul Hameed P*^a and Sudha Ravishankar*^a

Author affiliations

* Corresponding authors

^a Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India
E-mail: shahulmehar0615@gmail.com, mailsuravi01@gmail.com

^b Global Alliance for TB Drug Development, 40 Wall Street, 24th Floor, New York, NY 10005, USA

^c AstraZeneca, Alderley Park, Mereside, Cheshire, UK

^d University of Pennsylvania, 111 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104, USA

Abstract

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.

MedChemComm

Scaffold morphing leading to evolution of 2,4-diaminoquinolines and aminopyrazolopyrimidines as inhibitors of the ATP synthesis pathway†‡

Abstract

Supplementary files

Article information

Download Citation

Author version available

Permissions

Scaffold morphing leading to evolution of 2,4-diaminoquinolines and aminopyrazolopyrimidines as inhibitors of the ATP synthesis pathway

Search articles by author

Spotlight

Advertisements