title: Synthesis of bi-substrate state mimics of dihydropteroate synthase as potential inhibitors and molecular probes.
abstract: The increasing emergence of resistant bacteria drives us to design and develop new antimicrobial agents. Pursuant to that goal, a new targeting approach of the dihydropteroate synthase enzyme, which serves as the site of action for the sulfonamide class of antimicrobial agents, is being explored. Using structural information, a new class of transition state mimics has been designed and synthesized that have the capacity to bind to the pterin, phosphate and para-amino binding sites. The design, synthesis and evaluation of these compounds as inhibitors of Bacillusanthracis dihydropteroate synthase is described herein. Outcomes from this work have identified the first trivalent inhibitors of dihydropteroate synthase whose activity displayed slow binding inhibition. The most active compounds in this series contained an oxidized pterin ring. The binding of these inhibitors was modeled into the dihydropteroate synthase active site and demonstrated a good correlation with the observed bioassay data, as well as provided important insight for the future design of higher affinity transition state mimics.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 847 Monroe Ave., Rm327, Memphis, TN 38613, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Qi
authors.forename: Kristopher G
authors.initials: KG
authors.lastname: Virga
authors.forename: Sourav
authors.initials: S
authors.lastname: Das
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Yun
authors.forename: Stephen W
authors.initials: SW
authors.lastname: White
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000187:drug effects / Q000201:enzymology; D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D015335:Molecular Probes; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011622:Pterins / Q000737:chemistry; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D015335:Molecular Probes; D063065:Organophosphonates; D011622:Pterins; D011744:Pyrimidinones; D013449:Sulfonamides; D004094:Dihydropteroate Synthase