title: Structure guided lead generation for M. tuberculosis thymidylate kinase (Mtb TMK): discovery of 3-cyanopyridone and 1,6-naphthyridin-2-one as potent inhibitors.
abstract: M. tuberculosis thymidylate kinase (Mtb TMK) has been shown in vitro to be an essential enzyme in DNA synthesis. In order to identify novel leads for Mtb TMK, we performed a high throughput biochemical screen and an NMR based fragment screen through which we discovered two novel classes of inhibitors, 3-cyanopyridones and 1,6-naphthyridin-2-ones, respectively. We describe three cyanopyridone subseries that arose during our hit to lead campaign, along with cocrystal structures of representatives with Mtb TMK. Structure aided optimization of the cyanopyridones led to single digit nanomolar inhibitors of Mtb TMK. Fragment based lead generation, augmented by crystal structures and the SAR from the cyanopyridones, enabled us to drive the potency of our 1,6-naphthyridin-2-one fragment hit from 500 μM to 200 nM while simultaneously improving the ligand efficiency. Cyanopyridone derivatives containing sulfoxides and sulfones showed cellular activity against M. tuberculosis. To the best of our knowledge, these compounds are the first reports of non-thymidine-like inhibitors of Mtb TMK.
authors.affiliation: Department of Chemistry, and ‡Department of Bioscience, Innovative Medicines Infection, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore, Karnataka 560024, India.
authors.forename: Maruti
authors.initials: M
authors.lastname: Naik
authors.forename: Anandkumar
authors.initials: A
authors.lastname: Raichurkar
authors.forename: Balachandra S
authors.initials: BS
authors.lastname: Bandodkar
authors.forename: Begur V
authors.initials: BV
authors.lastname: Varun
authors.forename: Shantika
authors.initials: S
authors.lastname: Bhat
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kalkhambkar
authors.forename: Kannan
authors.initials: K
authors.lastname: Murugan
authors.forename: Rani
authors.initials: R
authors.lastname: Menon
authors.forename: Jyothi
authors.initials: J
authors.lastname: Bhat
authors.forename: Beena
authors.initials: B
authors.lastname: Paul
authors.forename: Harini
authors.initials: H
authors.lastname: Iyer
authors.forename: Syeed
authors.initials: S
authors.lastname: Hussein
authors.forename: Julie A
authors.initials: JA
authors.lastname: Tucker
authors.forename: Martin
authors.initials: M
authors.lastname: Vogtherr
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Embrey
authors.forename: Helen
authors.initials: H
authors.lastname: McMiken
authors.forename: Swati
authors.initials: S
authors.lastname: Prasad
authors.forename: Adrian
authors.initials: A
authors.lastname: Gill
authors.forename: Bheemarao G
authors.initials: BG
authors.lastname: Ugarkar
authors.forename: Janani
authors.initials: J
authors.lastname: Venkatraman
authors.forename: Jon
authors.initials: J
authors.lastname: Read
authors.forename: Manoranjan
authors.initials: M
authors.lastname: Panda
mesh_terms: D001665:Binding Sites; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D013940:Thymidylate Synthase