Studies on the reaction of ortho-diamines with trifluoropyruvaldehyde, 1,1,1-trifluorobutane-2,3-dione, hexafluoropropene oxide, and methyl trifluoropyruvate, and its application to the synthesis of riboflavin synthase inhibitors

Hemantkumar Hiralal Patel, Purdue University

Abstract

The inhibition of riboflavin biosynthesis provides a strategy for the development of therapeutically useful antibiotics. Selective toxicity to the parasite and not the host could be achieved, because pathogenic microorganisms must make their own riboflavin by biosynthesis, while mammals obtain this vitamin from dietary sources. With the aim to synthesize 6- or 7-trifluoromethyl substituted 8-(D-ribityl) lumazines, model studies were carried out involving reactions of trifluoropyruvaldehyde and 1,1,1-trifluorbutane-2,3-dione with ortho-diamines. The scope of the reaction and regiochemistry of the products have been established. Two substrate analogs of riboflavin synthase, 8-(D-ribityl)-6-(trifluoromethyl)lumazine (59) and 7-methyl-8-(D-ribityl)-6-(trifluoromethyl)lumazine (61) have been synthesized. A transition state analog of riboflavin synthase, 7-oxo-8-(D-ribityl)-6-(trifluoromethyl)lumazine (64) has also been synthesized. Reaction of methyl trifluoropyruvate with ortho-diamines was also investigated. The substrate analog 59 (K$\sb{\rm i}$ = 70 $\mu$M) and the transition state analog 64 (K$\sb{\rm i}$ = 100 $\mu$M) were found to be weak inhibitors of riboflavin synthase of Bacillus subtilis. The enzyme binding studies of compound 59 with light riboflavin synthase of Bacillus subtilis have demonstrated that fluorolumazines might be useful as $\sp{19}$F NMR detecting shift probes to study the mechanism of the dismutation reaction in riboflavin biosynthesis.

Degree

Ph.D.

Advisors

Cushman, Purdue University.

Subject Area

Pharmacology

COinS