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 Bacillus anthracis 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.

Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications

“…Some alternatives have been proposed during the last years as early steps for future drug development [116,117]. This is the case of the recent work of Dennis et al, where they not only synthesized derivatives of 8-mercaptoguanine (a pterin-like compound) that inhibit DHPS by targeting DHP-PPi pocket with great potency (sub-micromolar affinities) but also inhibited other enzymes of the folate cycle such as 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase, which catalyzes the previous reaction to DHPS-mediated one [118].…”

Replacing Sulfa Drugs with Novel Dhps Inhibitors

“…Several years before obtaining the near transition state structure of DHPS, the authors attempted to design transition-state analog inhibitors that simultaneously contact the pterin-, p ABA- and PPi-binding pockets [44]. Two of the four compounds synthesized display in vitro activity against purified Ba DHPS and show evidence of slow-binding kinetics (Figure 8).…”

Structure‐Based Design of Novel Pyrimido[4,5‐c]pyridazine Derivatives as Dihydropteroate Synthase Inhibitors with Increased Affinity

“…The pterin binding site is therefore a very attractive alternative target for the design and development of novel antimicrobial agents, and we have been pursuing this goal. [17, 18] …”