Discovery and Structure Activity Relationship Optimization of a Novel Rv1625c Agonist Chemotype with Antitubercular Activity
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.
Show 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.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Nitroimidazopyrazinones with oral activity against tuberculosis and Chagas disease in mouse models of infection 94%
- Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 that Exhibits Antiviral Efficacy in SARS-CoV-2 Infected African Green Monkeys 93%
- Development of potent and selective CK1α Molecular Glue Degraders 93%
Similar papers in this journal
- Legacy 4(1H)-quinolone scaffolds activity against acute and chronic Toxoplasma gondii infection 95%
- Identification of α-azacyclic acetamide-based inhibitors of P. falciparum Na+ pump (PfATP4) with fast-killing asexual blood-stage antimalarial activity by phenotypic screening 94%
- High-throughput screening of more than 30,000 compounds for anthelmintics against gastrointestinal nematode parasites 93%
Similar papers in this journal
- Identification of new MmpL3 inhibitors by untargeted and targeted mutant screens defines MmpL3 domains with differential resistance 95%
- GSK2556286 is a novel antitubercular drug candidate effective in vivo with the potential to shorten tuberculosis treatment 94%
- Lead optimisation of dehydroemetine for repositioned use in malaria 93%
Similar papers in this journal
- Identification of kinase inhibitors as potential host-directed therapies for intracellular bacteria 93%
- Disrupting Notch signalling by a small molecule inhibiting dihydroorotate dehydrogenase activity 93%
- HTRF-based identification of small molecules targeting SARS-CoV-2 E protein interaction with ZO-1 PDZ2 92%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.