86296-75-5Relevant articles and documents
8-Mercaptoguanine Derivatives as Inhibitors of Dihydropteroate Synthase
Dennis, Matthew L.,Lee, Michael D.,Harjani, Jitendra R.,Ahmed, Mohamed,DeBono, Aaron J.,Pitcher, Noel P.,Wang, Zhong-Chang,Chhabra, Sandeep,Barlow, Nicholas,Rahmani, Rapha?l,Cleary, Ben,Dolezal, Olan,Hattarki, Meghan,Aurelio, Luigi,Shonberg, Jeremy,Graham, Bim,Peat, Thomas S.,Baell, Jonathan B.,Swarbrick, James D.
, p. 1922 - 1930 (2018)
Dihydropteroate synthase (DHPS) is an enzyme of the folate biosynthesis pathway, which catalyzes the formation of 7,8-dihydropteroate (DHPt) from 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (DHPPP) and para-aminobenzoic acid (pABA). DHPS is the long-standing target of the sulfonamide class of antibiotics that compete with pABA. In the wake of sulfa drug resistance, targeting the structurally rigid (and more conserved) pterin site has been proposed as an alternate strategy to inhibit DHPS in wild-type and sulfa drug resistant strains. Following the work on developing pterin-site inhibitors of the adjacent enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), we now present derivatives of 8-mercaptoguanine, a fragment that binds weakly within both enzymes, and quantify sub-μm binding using surface plasmon resonance (SPR) to Escherichia coli DHPS (EcDHPS). Eleven ligand-bound EcDHPS crystal structures delineate the structure–activity relationship observed providing a structural framework for the rational development of novel, substrate-envelope-compliant DHPS inhibitors.
Monocyclic Pteridine Analogues. Inhibition of Escherichia coli Dihydropteroate Synthase by 6-Amino-5-nitrosoisocytosines
Lever, O. William,Bell, Lawrence N.,McGuire, H. Michael,Ferone, Robert
, p. 1870 - 1874 (2007/10/02)
A variety of 5,6-disubstituted isocytosine derivatives were evaluated in vitro as inhibitors of dihydropteroate synthase from Escherichia coli.A number of 6-(alkylamino)-5-nitrosoisocytosines have in vitro potency equivalent with or superior to that of therapeutically effective sulfonamide inhibitors of the synthase.The sulfonamide drugs are known to complete for the p-aminobenzoic acid binding site of the synthase, and kinetic analysis of inhibition of the synthase by 6-(methylamino)-5-nitrosoisocytosine (16; I50 = 1.6 μM) and by the 6-(3-phenoxypropyl)amino analogue (33; I50 = 3.7 μM) indicated that the nitrosoisocytosine inhibitors compete with the pteridine substrate for the enzyme.Structure-activity studies demonstrated that the enzyme surface has a low tolerance for steric bulk in the region surrounding the isocytosine 6-amino function.However, this steric intolerance may be counterbalanced to a significant degree by positive allosteric interactions achieved by certain analogues that have a 6-(ω-phenylalkyl)amino substituent.For example, 6--5-nitrosoisocytosine (28) is as effective an inhibitor (I50 = 1.4 μM) as the 6-methylamino compound 16.Although several members of the 5-nitroso series were potent synthase inhibitors, none of the nitrosoisocytosines exhibited significant antibacterial activity.This observation may reflect poor transport of these compounds through the bacterial cell wall or, alternatively, may result from a rapid metabolic inactivation process.