1064652-85-2Relevant articles and documents
Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents
Hajian, Behnoush,Scocchera, Eric,Shoen, Carolyn,Krucinska, Jolanta,Viswanathan, Kishore,G-Dayanandan, Narendran,Erlandsen, Heidi,Estrada, Alexavier,Miku?ová, Katarína,Korduláková, Jana,Cynamon, Michael,Wright, Dennis
, p. 781 - 6,791 (2019)
The folate biosynthetic pathway offers many druggable targets that have yet to be exploited in tuberculosis therapy. Herein, we have identified a series of small molecules that interrupt Mycobacterium tuberculosis (Mtb) folate metabolism by dual targeting of dihydrofolate reductase (DHFR), a key enzyme in the folate pathway, and its functional analog, Rv2671. We have also compared the antifolate activity of these compounds with that of para-aminosalicylic acid (PAS). We found that the bioactive metabolite of PAS, in addition to previously reported activity against DHFR, inhibits flavin-dependent thymidylate synthase in Mtb, suggesting a multi-targeted mechanism of action for this drug. Finally, we have shown that antifolate treatment in Mtb decreases the production of mycolic acids, most likely due to perturbation of the activated methyl cycle. We conclude that multi-targeting of the folate pathway in Mtb is associated with highly potent anti-mycobacterial activity. Hajian et al. have investigated the inhibitory activity of a series of small-molecule antifolates and para-aminosalicylic acid against Mycobacterium tuberculosis, the causative agent of tuberculosis, and show that these compounds exert their activity by acting on multiple targets within the folate biosynthetic pathway.
Salicylanilides: Selective inhibitors of interleukin-12p40 production
Brown, Michael E.,Fitzner, Jeffrey N.,Stevens, Tracey,Chin, Wilson,Wright, Clifford D.,Boyce, Jim P.
experimental part, p. 8760 - 8764 (2009/04/05)
Interleukin (IL)-12p40, a subunit component of both IL-12 and IL-23, is being widely studied for its role in inflammatory disease. As part of an effort to profile cellular signaling pathways across different cell types, we report salicylanilide inhibitors of IL-12p40 production in stimulated dendritic cells. Based on a hypothesis that a desirable therapeutic profile is one that could block IL-12p40 but not IL-6 production, we engaged in directed analoging. This resulted in salicylanilides with similar IL-12p40 related potency but enhanced selectivity relative to IL-6 production.
