title: Synthesis of new generation triazolyl- and isoxazolyl-containing 6-nitro-2,3-dihydroimidazooxazoles as anti-TB agents: in vitro, structure-activity relationship, pharmacokinetics and in vivo evaluation.
abstract: The nitroimidazole scaffold has attracted great interest in the last decade, which ultimately led to the discovery of the successful drug Delamanid for multi-drug resistant tuberculosis (MDR-TB). Herein, we report medicinal chemistry on a 6-nitro-2,3-dihydroimidazooxazole (NHIO) scaffold with SAR on the novel series of triazolyl- and isoxazolyl-based NHIO compounds. In the present study, 41 novel triazolyl- and isoxazolyl-based NHIO compounds were synthesized and evaluated against Mycobacterium tuberculosis (MTB) H37Rv. The active compounds with MIC of 0.57-0.13 μM were further screened against dormant, as well as against resistant strains of MTB. Based on the overall in vitro profile, five compounds were studied for in vivo oral pharmacokinetics, wherein two compounds: 1g and 2e showed a good PK profile. In in vivo efficacy studies in the intra-nasal model of acute infection, 1g showed 1.8 and 1 log CFU reduction with respect to the untreated and early control, respectively. The lead compound 1g also showed an additive to synergistic effect in combination studies with first line-TB drugs and no CYP inhibition. From the present studies, the compound 1g represents another alternative lead candidate in this class and needs further detailed investigation.
authors: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India. ppsingh@iiim.ac.in ram@iiim.ac.in iakhan@iiim.ac.in.
authors: Gurunadham
authors: G
authors: Munagala
authors: Kushalava Reddy
authors: KR
authors: Yempalla
authors: Samsher
authors: S
authors: Singh
authors: Sumit
authors: S
authors: Sharma
authors: Nitin Pal
authors: NP
authors: Kalia
authors: Vikrant Singh
authors: VS
authors: Rajput
authors: Sunil
authors: S
authors: Kumar
authors: Sanghapal D
authors: SD
authors: Sawant
authors: Inshad Ali
authors: IA
authors: Khan
authors: Ram A
authors: RA
authors: Vishwakarma
authors: Parvinder Pal
authors: PP
authors: Singh
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D056945:Hep G2 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D007527:Isoenzymes; D010080:Oxazoles; D003577:Cytochrome P-450 Enzyme System