title: Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure-activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-β-D-ribose 2'-oxidase.
abstract: We report the discovery of benzothiazoles, a novel anti-mycobacterial series, identified from a whole cell based screening campaign. Benzothiazoles exert their bactericidal activity against Mycobacterium tuberculosis (Mtb) through potent inhibition of decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1), the key enzyme involved in arabinogalactan synthesis. Specific target linkage and mode of binding were established using co-crystallization and protein mass spectrometry studies. Most importantly, the current study provides insights on the utilization of systematic medicinal chemistry approaches to mitigate safety liabilities while improving potency during progression from an initial genotoxic hit, the benzothiazole N-oxides (BTOs) to the lead-like AMES negative, crowded benzothiazoles (cBTs). These findings offer opportunities for development of safe clinical candidates against tuberculosis. The design strategy adopted could find potential application in discovery of safe drugs in other therapy areas too.
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Landge
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Amrita B
authors.initials: AB
authors.lastname: Mullick
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Nagalapur
authors.affiliation: École Polytechnique Fédérale de Lausanne, Global Health Institute, Switzerland.
authors.forename: João
authors.initials: J
authors.lastname: Neres
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Venkita
authors.initials: V
authors.lastname: Subbulakshmi
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Kannan
authors.initials: K
authors.lastname: Murugan
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Anirban
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Global Safety Assessment, AstraZeneca, Alderley Park, Mereside, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Sadler
authors.affiliation: Global Safety Assessment, AstraZeneca, Alderley Park, Mereside, UK.
authors.forename: Mick D
authors.initials: MD
authors.lastname: Fellows
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Humnabadkar
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Jyothi
authors.initials: J
authors.lastname: Mahadevaswamy
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Prakash
authors.initials: P
authors.lastname: Vachaspati
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Parvinder
authors.initials: P
authors.lastname: Kaur
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Mallya
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Rudrapatna
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Disha
authors.initials: D
authors.lastname: Awasthy
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
authors.affiliation: École Polytechnique Fédérale de Lausanne, Global Health Institute, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Pojer
authors.affiliation: École Polytechnique Fédérale de Lausanne, Global Health Institute, Switzerland.
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Tanjore S
authors.initials: TS
authors.lastname: Balganesh
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Bheemarao G
authors.initials: BG
authors.lastname: Ugarkar
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: V
authors.initials: V
authors.lastname: Balasubramanian
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Balachandra S
authors.initials: BS
authors.lastname: Bandodkar
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
authors.forename: Manoranjan
authors.initials: M
authors.lastname: Panda
authors.affiliation: iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India. Electronic address: vasanthi_epr@yahoo.com.
authors.forename: Vasanthi
authors.initials: V
authors.lastname: Ramachandran
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052160:Benzothiazoles / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D052160:Benzothiazoles; D000429:Alcohol Oxidoreductases; C583625:DprE1 protein, Mycobacterium tuberculosis; C005465:benzothiazole
keywords: AMES; Antimycobacterial; Benzothiazoles; DprE1; Genotoxic