Synthesis, Bioactivity and SAR study of N′-(5-substituted-1,3,4-thiadiazol-2-yl)-N-cyclopropylformyl-thioureas as ketol-acid reductoisomerase Inhibitors

Abstract

Ketol-acid reductoisomerase (KARI; EC 1.1.1.86) catalyzes the second common step in branched-chain amino acid biosynthesis. The catalyzed process consists of two steps, the first of which is an alkyl migration from one carbon atom to its neighboring atom. The likely transition state is a cyclopropane derivative, thus a new series of cyclopropanecarbonyl thiourea derivatives were designed and synthesized involving a one-pot phase transfer catalyzed reaction. Rice KARI inhibitory activity of these compounds were evaluated and the 5-butyl substituted (3e) and 3-pyridinyl substituted (3n) compounds reached 100% at 100μg·mL^{− 1}. Structure-activity relationship shows that longer chain derivatives had higher KARI inhibitory activity. Meanwhile substitution of the 4-position of the benzene ring had higher KARI inhibitory activity than that of the 2 and 3-position. Auto-Dock was used to predict the binding mode of 3n. This was done by analyzing the interaction of compound 3n with the active sites of the available spinach KARI. This was in accord with the results analyzed by the frontier molecular orbital theory.

Keywords::

• Cyclopropane derivatives
• Auto-Dock
• KARI activity
• thiourea
• inhibition
• Ketol-acid reductoisomerase

Acknowledgements

This work was supported by the National Basic Research Key Program of China (No. 2003CB114406), the National Natural Science Foundation Key Project of China (No. 20432010), the High Performance Computing Project of Tianjin Ministry of Science and Technology of China (No. 043185111-5), Specialized Research Fund for the Doctoral Program of Higher Education (No. 20070055044) and Tianjin Natural Science Foundation (No.08JCYBJC00800).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.