Discovery and Structure Activity Relationship Optimization of a Novel Rv1625c Agonist Chemotype with Antitubercular Activity

Authors

Xie, H., Sukheja, P., Tolentino, K., Webb, J., Woods, A., Chi, V., Kathayat, D., Montague, C. R., VanderVen, B. C., Winneroski, L., Durst, G., Mendel, D., Hipskind, P., Henry, K., McNamara, C. W., Yang, B., Chatterjee, A. K.

Abstract

Rv1625c/Cya has emerged as a promising target for the development of treatment-shortening therapies for tuberculosis. Screening of an Enamine compound library identified sBQQ004 as an initial hit, and rapid hit optimization led to compound 1, which was subsequently confirmed as an Rv1625c/Cya agonist. Structure activity relationship studies identified lead compound 25 with potent activity against Mycobacterium tuberculosis H37Rv under cholesterol-dependent growth conditions (MIC = 0.27 uM) and strong intramacrophage activity (EC50 = 0.079 uM). Compounds 1 and 25 showed oral bioavailabilities of 84.5% and 51.9% in mice, respectively. Repeat BID dosing of compound 1 resulted in a dose- and time-dependent decrease in systemic exposure. Despite this pharmacokinetic limitation, the potency and overall profile of this chemotype encouraged continued optimization.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 20 Sep 2026.

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