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 tube...

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Published in:ACS medicinal chemistry letters 2015-10, Vol.6 (10), p.1059-1064
Main Authors: Yempalla, Kushalava Reddy, Munagala, Gurunadham, Singh, Samsher, Kour, Gurleen, Sharma, Shweta, Chib, Reena, Kumar, Sunil, Wazir, Priya, Singh, G. D, Raina, Sushil, Bharate, Sonali S, Khan, Inshad Ali, Vishwakarma, Ram A, Singh, Parvinder Pal
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Language:English
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Summary: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 (RifR 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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.5b00202