title: 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.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Subramanyam J
authors.initials: SJ
authors.lastname: Tantry
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Shankar D
authors.initials: SD
authors.lastname: Markad
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Shinde
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Jyothi
authors.initials: J
authors.lastname: Bhat
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Balakrishnan
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Amit K
authors.identifier: 0000-0002-2901-1075
authors.initials: AK
authors.lastname: Gupta
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Anisha
authors.initials: A
authors.lastname: Ambady
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Anandkumar
authors.initials: A
authors.lastname: Raichurkar
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Chaitanyakumar
authors.initials: C
authors.lastname: Kedari
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Naina V
authors.initials: NV
authors.lastname: Mudugal
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Narayan
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: C N
authors.initials: CN
authors.lastname: Naveen Kumar
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Robert
authors.initials: R
authors.lastname: Nanduri
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Bharath
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Jitendar
authors.initials: J
authors.lastname: Reddy
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Vijender
authors.initials: V
authors.lastname: Panduga
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: K R
authors.initials: KR
authors.lastname: Prabhakar
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Kandaswamy
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Ramanatha
authors.initials: R
authors.lastname: Saralaya
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Parvinder
authors.initials: P
authors.lastname: Kaur
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Neela
authors.initials: N
authors.lastname: Dinesh
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Supreeth
authors.initials: S
authors.lastname: Guptha
authors.affiliation: AstraZeneca , Alderley Park, Mereside, Macclesfield, Cheshire U.K. SK10 4TG.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Rich
authors.affiliation: AstraZeneca , Alderley Park, Mereside, Macclesfield, Cheshire U.K. SK10 4TG.
authors.forename: David
authors.initials: D
authors.lastname: Murray
authors.affiliation: AstraZeneca , Alderley Park, Mereside, Macclesfield, Cheshire U.K. SK10 4TG.
authors.forename: Helen
authors.initials: H
authors.lastname: Plant
authors.affiliation: AstraZeneca , Alderley Park, Mereside, Macclesfield, Cheshire U.K. SK10 4TG.
authors.forename: Marian
authors.initials: M
authors.lastname: Preston
authors.affiliation: AstraZeneca , Alderley Park, Mereside, Macclesfield, Cheshire U.K. SK10 4TG.
authors.forename: Helen
authors.initials: H
authors.lastname: Ashton
authors.affiliation: AstraZeneca , Alderley Park, Mereside, Macclesfield, Cheshire U.K. SK10 4TG.
authors.forename: Darren
authors.initials: D
authors.lastname: Plant
authors.affiliation: AstraZeneca , Alderley Park, Mereside, Macclesfield, Cheshire U.K. SK10 4TG.
authors.forename: Jarrod
authors.initials: J
authors.lastname: Walsh
authors.affiliation: AstraZeneca , Alderley Park, Mereside, Macclesfield, Cheshire U.K. SK10 4TG.
authors.forename: Peter
authors.initials: P
authors.lastname: Alcock
authors.affiliation: AstraZeneca , Alderley Park, Mereside, Macclesfield, Cheshire U.K. SK10 4TG.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Naylor
authors.affiliation: AstraZeneca , Alderley Park, Mereside, Macclesfield, Cheshire U.K. SK10 4TG.
authors.forename: Matthew
authors.initials: M
authors.lastname: Collier
authors.affiliation: Infection Innovative Medicines, AstraZeneca , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: James
authors.initials: J
authors.lastname: Whiteaker
authors.affiliation: Infection Innovative Medicines, AstraZeneca , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Robert E
authors.initials: RE
authors.lastname: McLaughlin
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Mallya
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Manoranjan
authors.initials: M
authors.lastname: Panda
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Rudrapatna
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Vasanthi
authors.initials: V
authors.lastname: Ramachandran
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Radha
authors.initials: R
authors.lastname: Shandil
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
authors.affiliation: Global Alliance for TB Drug Development , 40 Wall Street, 24th Floor, New York, New York 10005, United States.
authors.forename: Khisi
authors.initials: K
authors.lastname: Mdluli
authors.affiliation: Global Alliance for TB Drug Development , 40 Wall Street, 24th Floor, New York, New York 10005, United States.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Cooper
authors.affiliation: University of Pennsylvania , 111 Clinical Research Building, 415 Curie Boulevard, Philadelphia Pennsylvania 19104, United States.
authors.forename: Harvey
authors.initials: H
authors.lastname: Rubin
authors.affiliation: University of Pennsylvania , 111 Clinical Research Building, 415 Curie Boulevard, Philadelphia Pennsylvania 19104, United States.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yano
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Pravin
authors.initials: P
authors.lastname: Iyer
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Shridhar
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: AstraZeneca , Alderley Park, Mereside, Macclesfield, Cheshire U.K. SK10 4TG.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kavanagh
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Kakoli
authors.initials: K
authors.lastname: Mukherjee
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: V
authors.initials: V
authors.lastname: Balasubramanian
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Vinayak P
authors.initials: VP
authors.lastname: Hosagrahara
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Solapure
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Sudha
authors.identifier: 0000-0002-5881-3130
authors.initials: S
authors.lastname: Ravishankar
authors.affiliation: Innovative Medicines, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Shahul
authors.initials: S
authors.lastname: Hameed P
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004987:Ethers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011803:Quinine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D004987:Ethers; D011725:Pyridines; C000609819:squaramide; D000255:Adenosine Triphosphate; D011803:Quinine