Structure guided lead generation for M. tuberculosis thymidylate kinase (Mtb TMK): discovery of 3-cyanopyridone and 1,6-naphthyridin-2-one as potent inhibitors.
| 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. |
|---|---|
| Authors: | Naik M; Department of Chemistry, and ‡Department of Bioscience, Innovative Medicines Infection, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore, Karnataka 560024, India.; Raichurkar A; Bandodkar BS; Varun BV; Bhat S; Kalkhambkar R; Murugan K; Menon R; Bhat J; Paul B; Iyer H; Hussein S; Tucker JA; Vogtherr M; Embrey KJ; McMiken H; Prasad S; Gill A; Ugarkar BG; Venkatraman J; Read J; Panda M |
| Source: | Journal of medicinal chemistry [J Med Chem] 2015 Jan 22; Vol. 58 (2), pp. 753-66. Date of Electronic Publication: 2014 Dec 23. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Washington Dc : American Chemical Society; Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| MeSH Terms: | Enzyme Inhibitors/*chemical synthesis ; Mycobacterium tuberculosis/*drug effects ; Thymidylate Synthase/*antagonists & inhibitors; Enzyme Inhibitors/pharmacology ; Mycobacterium tuberculosis/enzymology ; Thymidylate Synthase/chemistry ; Binding Sites ; Drug Discovery ; High-Throughput Screening Assays ; Humans ; Magnetic Resonance Spectroscopy ; Structure-Activity Relationship |
| 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. |
| Molecular Sequence: | PDB 4UNN; 4UNP; 4UNQ; 4UNR; 4UNS |
| Substance Nomenclature: | 0 (Enzyme Inhibitors); EC 2.1.1.45 (Thymidylate Synthase) |
| Entry Date(s): | Date Created: 20141209 Date Completed: 20150331 Latest Revision: 20150122 |
| Update Code: | 20260130 |
| DOI: | 10.1021/jm5012947 |
| PMID: | 25486447 |
| Database: | MEDLINE |
Journal Article