Lumazine synthase inhibitors: Part I. Structure-based design and synthesis. Part II. Design and discovery of a novel high throughput screening method

Jinhua Chen, Purdue University

Abstract

Riboflavin is essential to all organisms. Higher animals, including man, must obtain it through their diet. Many pathogenic microorganisms lack the uptake system for riboflavin and depend on the endogenous synthesis of riboflavin. This study aims to the design and discovery of inhibitors of the riboflavin biosynthesis pathway as potential antibiotics. Analogs of both substrates and bi-substrate analogs were designed and synthesized based on crystal structure and hypothetical reaction mechanism. Bi-substrate analogs were relatively more potent than analogs of either substrate. Phosphonate-bearing bi-substrate analogs were more potent for M. tuberculosis lumazine synthase in a phosphate free buffer than B. subtilis lumazine synthase in a phosphate buffer. Bi-substrate analogs without a ribityl group also showed good activities. A novel high throughput screening method was discovered for fast, economical, and reliable screening of potential lumazine synthase inhibitors. Preliminary testing showed that this method distinguished all active compounds from inactive compounds.

Degree

Ph.D.

Advisors

Cushman, Purdue University.

Subject Area

Pharmacology

COinS