title: 2-Phenylindole and Arylsulphonamide: Novel Scaffolds Bactericidal against Mycobacterium tuberculosis.
abstract: A cellular activity-based screen on Mycobacterium tuberculosis (Mtb) H37Rv using a focused library from the AstraZeneca corporate collection led to the identification of 2-phenylindoles and arylsulphonamides, novel antimycobacterial scaffolds. Both the series were bactericidal in vitro and in an intracellular macrophage infection model, active against drug sensitive and drug resistant Mtb clinical isolates, and specific to mycobacteria. The scaffolds showed promising structure-activity relationships; compounds with submicromolar cellular potency were identified during the hit to lead exploration. Furthermore, compounds from both scaffolds were tested for inhibition of known target enzymes or pathways of antimycobacterial drugs including InhA, RNA polymerase, DprE1, topoisomerases, protein synthesis, and oxidative-phosphorylation. Compounds did not inhibit any of the targets suggesting the potential of a possible novel mode of action(s). Hence, both scaffolds provide the opportunity to be developed further as leads and tool compounds to uncover novel mechanisms for tuberculosis drug discovery.
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Maruti
authors.initials: M
authors.lastname: Naik
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Ghorpade
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Lalit Kumar
authors.initials: LK
authors.lastname: Jena
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Gorai
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Narayan
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Supreeth
authors.initials: S
authors.lastname: Guptha
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Neela
authors.initials: N
authors.lastname: Dinesh
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Parvinder
authors.initials: P
authors.lastname: Kaur
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Radha
authors.initials: R
authors.lastname: Nandishaiah
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Jyothi
authors.initials: J
authors.lastname: Bhat
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Balakrishnan
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Humnabadkar
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Vasanthi
authors.initials: V
authors.lastname: Ramachandran
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Lava Kumar
authors.initials: LK
authors.lastname: Naviri
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Khadtare
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Manoranjan
authors.initials: M
authors.lastname: Panda
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Pravin S
authors.initials: PS
authors.lastname: Iyer
authors.affiliation: Department of Medicinal Chemistry and Department of Biosciences, IMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Monalisa
authors.initials: M
authors.lastname: Chatterji
keywords: 2-phenylindoles; Mycobacterium tuberculosis; Tuberculosis; arylsulphonamides