title: 1,4-azaindole, a potential drug candidate for treatment of tuberculosis.
abstract: New therapeutic strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis are urgently required to combat the global tuberculosis (TB) threat. Toward this end, we previously reported the identification of 1,4-azaindoles, a promising class of compounds with potent antitubercular activity through noncovalent inhibition of decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1). Further, this series was optimized to improve its physicochemical properties and pharmacokinetics in mice. Here, we describe the short-listing of a potential clinical candidate, compound 2, that has potent cellular activity, drug-like properties, efficacy in mouse and rat chronic TB infection models, and minimal in vitro safety risks. We also demonstrate that the compounds, including compound 2, have no antagonistic activity with other anti-TB drugs. Moreover, compound 2 shows synergy with PA824 and TMC207 in vitro, and the synergy effect is translated in vivo with TMC207. The series is predicted to have a low clearance in humans, and the predicted human dose for compound 2 is ≤1 g/day. Altogether, our data suggest that a 1,4-azaindole (compound 2) is a promising candidate for the development of a novel anti-TB drug.
authors: Department of Biosciences, IMED Infection, AstraZeneca, Bangalore, India monalisa.chatterji@gmail.com radha.shandil@astrazeneca.com psshirude@gmail.com.
authors: Monalisa
authors: M
authors: Chatterji
authors: DMPK and Animal Sciences, IMED Infection, AstraZeneca, Bangalore, India monalisa.chatterji@gmail.com radha.shandil@astrazeneca.com psshirude@gmail.com.
authors: Radha
authors: R
authors: Shandil
authors: Department of Medicinal Chemistry, IMED Infection, AstraZeneca, Bangalore, India.
authors: M R
authors: MR
authors: Manjunatha
authors: DMPK and Animal Sciences, IMED Infection, AstraZeneca, Bangalore, India.
authors: Suresh
authors: S
authors: Solapure
authors: Department of Biosciences, IMED Infection, AstraZeneca, Bangalore, India.
authors: Vasanthi
authors: V
authors: Ramachandran
authors: DMPK and Animal Sciences, IMED Infection, AstraZeneca, Bangalore, India.
authors: Naveen
authors: N
authors: Kumar
authors: DMPK and Animal Sciences, IMED Infection, AstraZeneca, Bangalore, India.
authors: Ramanatha
authors: R
authors: Saralaya
authors: DMPK and Animal Sciences, IMED Infection, AstraZeneca, Bangalore, India.
authors: Vijender
authors: V
authors: Panduga
authors: DMPK and Animal Sciences, IMED Infection, AstraZeneca, Bangalore, India.
authors: Jitendar
authors: J
authors: Reddy
authors: DMPK and Animal Sciences, IMED Infection, AstraZeneca, Bangalore, India.
authors: K R
authors: KR
authors: Prabhakar
authors: Department of Biosciences, IMED Infection, AstraZeneca, Bangalore, India.
authors: Sreevalli
authors: S
authors: Sharma
authors: Safety Assessment, IMED, AstraZeneca, Alderly Park, Mereside, United Kingdom.
authors: Claire
authors: C
authors: Sadler
authors: Global Alliance for TB Drug Development, New York, New York, USA.
authors: Christopher B
authors: CB
authors: Cooper
authors: Global Alliance for TB Drug Development, New York, New York, USA.
authors: Khisi
authors: K
authors: Mdluli
authors: Department of Medicinal Chemistry, IMED Infection, AstraZeneca, Bangalore, India.
authors: Pravin S
authors: PS
authors: Iyer
authors: Department of Biosciences, IMED Infection, AstraZeneca, Bangalore, India.
authors: Shridhar
authors: S
authors: Narayanan
authors: Department of Medicinal Chemistry, IMED Infection, AstraZeneca, Bangalore, India monalisa.chatterji@gmail.com radha.shandil@astrazeneca.com psshirude@gmail.com.
authors: Pravin S
authors: PS
authors: Shirude
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004285:Dogs; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D007211:Indoles; D011725:Pyridines