Discovery of Imidazo[1,2-a]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis.

Abstract

The approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report the discovery of two diverse lead series imidazo[1,2-a]pyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial ATP synthesis. Through medicinal chemistry exploration, we established a robust structure-activity relationship of these two scaffolds, resulting in nanomolar potencies in an ATP synthesis inhibition assay. A biochemical deconvolution cascade suggested cytochrome c oxidase as the potential target of IPE class of molecules, whereas characterization of spontaneous resistant mutants of SQAs unambiguously identified ATP synthase as its molecular target. Absence of cross resistance against bedaquiline resistant mutants suggested a different binding site for SQAs on ATP synthase. Furthermore, SQAs were found to be noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis infection.

• Authors: Subramanyam J Tantry, Shankar D Markad, Vikas Shinde, Jyothi Bhat, Gayathri Balakrishnan, Amit K Gupta, Anisha Ambady, Anandkumar Raichurkar, Chaitanyakumar Kedari, Sreevalli Sharma, Naina V Mudugal, Ashwini Narayan, C N Naveen Kumar, Robert Nanduri, Sowmya Bharath, Jitendar Reddy, Vijender Panduga, K R Prabhakar, Karthikeyan Kandaswamy, Ramanatha Saralaya, Parvinder Kaur, Neela Dinesh, Supreeth Guptha, Kirsty Rich, David Murray, Helen Plant, Marian Preston, Helen Ashton, Darren Plant, Jarrod Walsh, Peter Alcock, Kathryn Naylor, Matthew Collier, James Whiteaker, Robert E McLaughlin, Meenakshi Mallya, Manoranjan Panda, Suresh Rudrapatna, Vasanthi Ramachandran, Radha Shandil, Vasan K Sambandamurthy, Khisi Mdluli, Christopher B Cooper, Harvey Rubin, Takahiro Yano, Pravin Iyer, Shridhar Narayanan, Stefan Kavanagh, Kakoli Mukherjee, V Balasubramanian, Vinayak P Hosagrahara, Suresh Solapure, Sudha Ravishankar, Shahul Hameed P
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 4 Pg. 1379-1399 (02 23 2017) ISSN: 1520-4804 [Electronic] United States
• PMID: 28075132 (Publication Type: Journal Article)

Chemical References

• Antitubercular Agents
• Ethers
• Pyridines
• squaramide
• Adenosine Triphosphate
• Quinine

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Antitubercular Agents (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Ethers (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Humans
• Mice
• Mice, Inbred BALB C
• Models, Molecular
• Mycobacterium tuberculosis (drug effects)
• Pyridines (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Quinine (analogs & derivatives, chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Tuberculosis (drug therapy, metabolism)