Nitrofuranyl Methyl Piperazines as New Anti-TB Agents: Identification, Validation, Medicinal Chemistry, and PK Studies.
Whole-cell screening of 20,000 drug-like small molecules led to the identification of nitrofuranyl methylpiperazines as potent anti-TB agents. In the present study, validation followed by medicinal chemistry has been used to explore the structure-activity relationship. Ten compounds demonstrated potent MIC in the range of 0.17-0.0072 μM against H37Rv Mycobacterium tuberculosis (MTB) and were further investigated against nonreplicating and resistant (Rif(R) and MDR) strains of MTB. These compounds were also tested for cytotoxicity. Among the 10 tested compounds, five showed submicromolar to nanomolar potency against nonreplicating and resistant (Rif(R) and MDR) strains of MTB along with a good safety index. Based on their overall in vitro profiles, the solubility and pharmacokinetic properties of five potent compounds were studied, and two analogues, 14f and 16g, were found to have comparatively better solubility than others tested and acceptable pharmacokinetic properties. This study presents the rediscovery of a nitrofuranyl class of compounds with improved aqueous solubility and acceptable oral PK properties, opening a new direction for further development.
Medicinal Chemistry Division, Clinical Microbiology Division, PK-PD and Toxicology Division, Pre-formulation Laboratory, Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Kushalava Reddy
KR
Yempalla
Medicinal Chemistry Division, Clinical Microbiology Division, PK-PD and Toxicology Division, Pre-formulation Laboratory, Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Gurunadham
G
Munagala
Medicinal Chemistry Division, Clinical Microbiology Division, PK-PD and Toxicology Division, Pre-formulation Laboratory, Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Samsher
S
Singh
Medicinal Chemistry Division, Clinical Microbiology Division, PK-PD and Toxicology Division, Pre-formulation Laboratory, Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Asmita
A
Magotra
Medicinal Chemistry Division, Clinical Microbiology Division, PK-PD and Toxicology Division, Pre-formulation Laboratory, Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Sunil
S
Kumar
Medicinal Chemistry Division, Clinical Microbiology Division, PK-PD and Toxicology Division, Pre-formulation Laboratory, Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Vikrant Singh
VS
Rajput
Medicinal Chemistry Division, Clinical Microbiology Division, PK-PD and Toxicology Division, Pre-formulation Laboratory, Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Sonali S
SS
Bharate
Medicinal Chemistry Division, Clinical Microbiology Division, PK-PD and Toxicology Division, Pre-formulation Laboratory, Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Manoj
M
Tikoo
Medicinal Chemistry Division, Clinical Microbiology Division, PK-PD and Toxicology Division, Pre-formulation Laboratory, Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
G D
GD
Singh
Medicinal Chemistry Division, Clinical Microbiology Division, PK-PD and Toxicology Division, Pre-formulation Laboratory, Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Inshad Ali
IA
Khan
Medicinal Chemistry Division, Clinical Microbiology Division, PK-PD and Toxicology Division, Pre-formulation Laboratory, Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180 001, India.
Ram A
RA
Vishwakarma
Medicinal Chemistry Division, Clinical Microbiology Division, PK-PD and Toxicology Division, Pre-formulation Laboratory, Academy of Scientific and Innovative Research, 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