Synthesis and Biological Evaluation of Polar Functionalities Containing Nitrodihydroimidazooxazoles as Anti-TB Agents.
Novel polar functionalities containing 6-nitro-2,3-dihydroimidazooxazole (NHIO) analogues were synthesized to produce a compound with enhanced solubility. Polar functionalities including sulfonyl, uridyl, and thiouridyl-bearing NHIO analogues were synthesized and evaluated against Mycobacterium tuberculosis (MTB) H37Rv. The aqueous solubility of compounds with MIC values ≤0.5 μg/mL were tested, and six compounds showed enhanced aqueous solubility. The best six compounds were further tested against resistant (Rif(R) and MDR) and dormant strains of MTB and tested for cytotoxicity in HepG2 cell line. Based on its overall in vitro characteristics and solubility profile, compound 6d was further shown to possess high microsomal stability, solubility under all tested biological conditions (PBS, SGF and SIF), and favorable oral in vivo pharmacokinetics and in vivo efficacy.
Medicinal Chemistry Division, Academy of Scientific and Innovative Research, Clinical Microbiology, PK-PD and Toxicology Division, and Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Kushalava Reddy
KR
Yempalla
Medicinal Chemistry Division, Academy of Scientific and Innovative Research, Clinical Microbiology, PK-PD and Toxicology Division, and Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Gurunadham
G
Munagala
Medicinal Chemistry Division, Academy of Scientific and Innovative Research, Clinical Microbiology, PK-PD and Toxicology Division, and Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Samsher
S
Singh
Medicinal Chemistry Division, Academy of Scientific and Innovative Research, Clinical Microbiology, PK-PD and Toxicology Division, and Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Gurleen
G
Kour
Medicinal Chemistry Division, Academy of Scientific and Innovative Research, Clinical Microbiology, PK-PD and Toxicology Division, and Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Shweta
S
Sharma
Medicinal Chemistry Division, Academy of Scientific and Innovative Research, Clinical Microbiology, PK-PD and Toxicology Division, and Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Reena
R
Chib
Medicinal Chemistry Division, Academy of Scientific and Innovative Research, Clinical Microbiology, PK-PD and Toxicology Division, and Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Sunil
S
Kumar
Medicinal Chemistry Division, Academy of Scientific and Innovative Research, Clinical Microbiology, PK-PD and Toxicology Division, and Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Priya
P
Wazir
Medicinal Chemistry Division, Academy of Scientific and Innovative Research, Clinical Microbiology, PK-PD and Toxicology Division, and Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
G D
GD
Singh
Medicinal Chemistry Division, Academy of Scientific and Innovative Research, Clinical Microbiology, PK-PD and Toxicology Division, and Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Sushil
S
Raina
Medicinal Chemistry Division, Academy of Scientific and Innovative Research, Clinical Microbiology, PK-PD and Toxicology Division, and Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Sonali S
SS
Bharate
Medicinal Chemistry Division, Academy of Scientific and Innovative Research, Clinical Microbiology, PK-PD and Toxicology Division, and Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Inshad Ali
IA
Khan
Medicinal Chemistry Division, Academy of Scientific and Innovative Research, Clinical Microbiology, PK-PD and Toxicology Division, and Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Ram A
RA
Vishwakarma
Medicinal Chemistry Division, Academy of Scientific and Innovative Research, Clinical Microbiology, PK-PD and Toxicology Division, and Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Parvinder Pal
PP
Singh
6-nitro-2,3-dihydroimidazooxazole; MTB H37Rv; Mycobacterium tuberculosis; multidrug resistant-TB; structure−activity relationship