title: Quinolinyl Pyrimidines: Potent Inhibitors of NDH-2 as a Novel Class of Anti-TB Agents.
abstract: NDH-2 is an essential respiratory enzyme in Mycobacterium tuberculosis (Mtb), which plays an important role in the physiology of Mtb. Herein, we present a target-based effort to identify a new structural class of inhibitors for NDH-2. High-throughput screening of the AstraZeneca corporate collection resulted in the identification of quinolinyl pyrimidines as the most promising class of NDH-2 inhibitors. Structure-activity relationship studies showed improved enzyme inhibition (IC50) against the NDH-2 target, which in turn translated into cellular activity against Mtb. Thus, the compounds in this class show a good correlation between enzyme inhibition and cellular potency. Furthermore, early ADME profiling of the best compounds showed promising results and highlighted the quinolinyl pyrimidine class as a potential lead for further development.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Pravin S
authors.initials: PS
authors.lastname: Shirude
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Beena
authors.initials: B
authors.lastname: Paul
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Roy Choudhury
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Kedari
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Balachandra
authors.initials: B
authors.lastname: Bandodkar
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd. , Avishkar, Bellary Road, Bangalore-560024, India.
authors.forename: Bheemarao G
authors.initials: BG
authors.lastname: Ugarkar
keywords: NDH-2; antituberculosis; quinolinyl pyrimidines; respiratory chain