Discovery of Novel 5-Benzylidenerhodanine and 5-Benzylidenethiazolidine-2,4-dione Inhibitors of MurD Ligase

Abstract

We have designed, synthesized, and evaluated 5-benzylidenerhodanine- and 5-benzylidenethiazolidine-2,4-dione-based compounds as inhibitors of bacterial enzyme MurD with E. coli IC(50) in the range 45-206 μM. The high-resolution crystal structure of MurD in complex with (R,Z)-2-(3-[{4-([2,4-dioxothiazolidin-5-ylidene]methyl)phenylamino}methyl)benzamido)pentanedioic acid [(R)-32] revealed details of the binding mode of the inhibitor within the active site and provides a good foundation for structure-based design of a novel generation of MurD inhibitors.

(Z)-3-Amino-5-(pyridin-2-ylmethylidene)-2-thioxo-1,3-thiazolidin-4-one

“…According to references [27][28][29][30][31], syntheses of these compounds result in (Z)-izomers. The same has recently been proved for 3-aminorhodanine derivatives [25].…”

Unexpected Synthesis of Novel 3-Allyl-5-(arylidene)-2-thioxo-thiazolidin-4-ones in Reactions of 3-Allylrhodanine with 2-Arylidene-4-methyl-5-oxopyrazolidinium Ylides

“…The unusual biological activities displayed by many rhodanine-based molecules have made them attractive synthetic targets. Arylidene rhodanines are generally prepared by reacting aldehydes and rhodanine in organic solvents and in the presence of organic bases [2,[9][10][11][12][13][14] .…”

MurD enzymes: some recent developments

“…In the next generation of 5-benzylidenethiazolidin-2,4-dione-and 5-benzylidenerhodanine-substituted glutamic acid, the substitution of the aromatic rings was altered, which resulted in E. coli MurD inhibitors (compounds 15 and 16, Scheme 6) with IC 50 values of 45 and 85 μmol/l, respectively (90). These compounds were further improved with minor alterations of the ring substituents and variations in the linker regions between the two phenyl rings.…”