title: Whole cell screen based identification of spiropiperidines with potent antitubercular properties.
abstract: Whole cell based screens to identify hits against Mycobacterium tuberculosis (Mtb), carried out under replicating and non-replicating (NRP) conditions, resulted in the identification of multiple, novel but structurally related spiropiperidines with potent antitubercular properties. These compounds could be further classified into three classes namely 3-(3-aryl-1,2,4-oxadiazol-5-yl)-1'-alkylspiro[indene-1,4'-piperidine] (abbr. spiroindenes), 4-(3-aryl-1,2,4-oxadiazol-5-yl)-1'-alkylspiro[chromene-2,4'-piperidine] (abbr. spirochromenes) and 1'-benzylspiro[indole-1,4'-piperidin]-2(1H)-one (abbr. spiroindolones). Spiroindenes showed ⩾ 4 log10 kill (at 2-12 μM) on replicating Mtb, but were moderately active under non replicating conditions. Whole genome sequencing efforts of spiroindene resistant mutants resulted in the identification of I292L mutation in MmpL3 (Mycobacterial membrane protein Large), required for the assembly of mycolic acid into the cell wall core of Mtb. MIC modulation studies demonstrated that the mutants were cross-resistant to spirochromenes but not to spiroindolones. This Letter describes lead identification efforts to improve potency while reducing the lipophilicity and hERG liabilities of spiroindenes. Additionally, as deduced from the SAR studies, we provide insights regarding the new chemical opportunities that the spiroindolones can offer to the TB drug discovery initiatives.
authors.affiliation: Department of Chemistry, AstraZeneca India Pvt. Ltd, India; Anthem Biosciences, Bangalore, India(§).
authors.forename: Subramanyam J
authors.initials: SJ
authors.lastname: Tantry
authors.affiliation: Department of Molecular Medicine, University of Padova, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Degiacomi
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Chemistry, AstraZeneca India Pvt. Ltd, India.
authors.forename: Lalit Kumar
authors.initials: LK
authors.lastname: Jena
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Narayan
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
authors.forename: Supreeth
authors.initials: S
authors.lastname: Guptha
authors.affiliation: Department of Chemistry, AstraZeneca India Pvt. Ltd, India; PI Industries Limited, Udaipur, India(§).
authors.forename: Gajanan
authors.initials: G
authors.lastname: Shanbhag
authors.affiliation: Department of Chemistry, AstraZeneca India Pvt. Ltd, India.
authors.forename: Sreenivasaiah
authors.initials: S
authors.lastname: Menasinakai
authors.affiliation: Department of Chemistry, AstraZeneca India Pvt. Ltd, India.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Mallya
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
authors.forename: Disha
authors.initials: D
authors.lastname: Awasthy
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Balakrishnan
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
authors.forename: Parvinder
authors.initials: P
authors.lastname: Kaur
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
authors.forename: Deepa
authors.initials: D
authors.lastname: Bhattacharjee
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, India; Department of Life Science, Pohang University of Science and Technology, Republic of Korea(§).
authors.forename: Chandan
authors.initials: C
authors.lastname: Narayan
authors.affiliation: DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd, India.
authors.forename: Jitendar
authors.initials: J
authors.lastname: Reddy
authors.affiliation: DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd, India.
authors.forename: C N
authors.initials: CN
authors.lastname: Naveen Kumar
authors.affiliation: DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd, India; Foundation for Neglected Disease Research, Bangalore, India(§).
authors.forename: Radha
authors.initials: R
authors.lastname: Shandil
authors.affiliation: Department of Molecular Medicine, University of Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Boldrin
authors.affiliation: Department of Molecular Medicine, University of Padova, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Ventura
authors.affiliation: Department of Molecular Medicine, University of Padova, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Manganelli
authors.affiliation: Global Health Institute, École polytechnique fédérale de Lausanne, Switzerland.
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Hartkoorn
authors.affiliation: Global Health Institute, École polytechnique fédérale de Lausanne, Switzerland.
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
authors.affiliation: Department of Chemistry, AstraZeneca India Pvt. Ltd, India; BMS Biocon Research Centre, Bangalore, India(§).
authors.forename: Manoranjan
authors.initials: M
authors.lastname: Panda
authors.affiliation: Department of Chemistry, AstraZeneca India Pvt. Ltd, India; Sanofi India Limited, Ankleshwar, India(§).
authors.forename: Shankar D
authors.initials: SD
authors.lastname: Markad
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, India.
authors.forename: Vasanthi
authors.initials: V
authors.lastname: Ramachandran
authors.affiliation: Department of Chemistry, AstraZeneca India Pvt. Ltd, India. Electronic address: sandeepghorpade@hotmail.com.
authors.forename: Sandeep R
authors.initials: SR
authors.lastname: Ghorpade
authors.affiliation: Department of Biosciences, AstraZeneca India Pvt. Ltd, India. Electronic address: neeladin@gmail.com.
authors.forename: Neela
authors.initials: N
authors.lastname: Dinesh
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D024881:Drug Resistance, Bacterial / Q000235:genetics; D016680:Genome, Bacterial; D057166:High-Throughput Screening Assays; D000860:Hypoxia; D008055:Lipids / Q000737:chemistry; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics; D010880:Piperidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D008055:Lipids; D010880:Piperidines; D013141:Spiro Compounds; D053509:Matrix Metalloproteinase 13
keywords: Antimycobacterial; Hypoxic conditions; MmpL3; Non-replicating phase; Whole cell screen; ss18b