29769-49-1Relevant 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 (2019/06/18)
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.
Pterin–sulfa conjugates as dihydropteroate synthase inhibitors and antibacterial agents
Zhao, Ying,Shadrick, William R.,Wallace, Miranda J.,Wu, Yinan,Griffith, Elizabeth C.,Qi, Jianjun,Yun, Mi-Kyung,White, Stephen W.,Lee, Richard E.
, p. 3950 - 3954 (2016/08/01)
The sulfonamide class of antibiotics has been in continuous use for over 70?years. They are thought to act by directly inhibiting dihydropteroate synthase (DHPS), and also acting as prodrugs that sequester pterin pools by forming dead end pterin–sulfonamide conjugates. In this study, eight pterin–sulfonamide conjugates were synthesized using a novel synthetic strategy and their biochemical and microbiological properties were investigated. The conjugates were shown to competitively inhibit DHPS, and inhibition was enhanced by the presence of pyrophosphate that is crucial to catalysis and is known to promote an ordering of the DHPS active site. The co-crystal structure of Yersinia pestis DHPS bound to one of the more potent conjugates revealed a mode of binding that is similar to that of the enzymatic product analog pteroic acid. The antimicrobial activities of the pterin–sulfonamide conjugates were measured against Escherichia coli in the presence and absence of folate precursors and dependent metabolites. These results show that the conjugates have appreciable antibacterial activity and act by an on target, anti-folate pathway mechanism rather than as simple dead end products.
Syntheses of labeled vitamers of folic acid to be used as internal standards in stable isotope dilution assays
Freisleben, Achim,Schieberle, Peter,Rychlik, Michael
, p. 4760 - 4768 (2007/10/03)
[2H4]Folic acid was synthesized by deuterating p-aminobenzoic acid, which was then coupled to glutamic acid and 6-formylpterin, Using [2H4]folic acid as starting component enabled the preparation of labeled vitamers tetrahydrofolate, 5-formyltetrahydrofolate, 5-methyltetrahydrofolate, and 10-formylfolate which were characterized by electrospray mass spectrometry and collision-induced dissociation. The mass spectrometric studies confirmed that the compounds could be used as internal standards in stable isotope dilution assays.
