risedronic acid In our previous work a new chemical entity I

In our previous work, a new chemical entity (IND-07) was proposed as an active moiety against Mtb-DHFR thereby increasing the chemical space for identification of NCE for tuberculosis. Compound IND-07 (Fig. 2) bears an indole moiety which has not been explored for antitubercular activity so far. IND-07 (1-(1-benzyl-5-hydroxy-2-methyl-1H-indol-3-yl) ethanone) was obtained through optimization of Hit 1 which was obtained through virtual screening of databases. Optimization of Hit 1 was done by designing a series of molecules by using different substitutions at 3, 5 positions of indole. IND-07 was found 6-fold selective towards Mtb-DHFR. These findings encouraged us to further dwell into the optimization of structure to improve the potency. The article herein presents the modification of IND-07 to further optimize the structural features of the risedronic acid to improve the biological activity through bioisosteric replacement of carboxylic group. IND-07 [4-((3-acetyl-1-benzyl-2-methyl-1H-indol-5-yl) oxy) butanoic acid] was converted to more potent derivatives (1-(1-benzyl-5-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-methyl-1H-indol-3-yl)ethanone) (KC-11) (Fig. 2) by replacing the carboxylic group at 5th position of indole by triazole derivatives. The synthesis of KC01-21, their in vitro antitubercular activity against H37RV, enzymatic Mtb-DHFR and h-DHFR inhibition are discussed in the section following.
Results and discussion
Conclusion The bioisosteric replacement of carboxylic group of IND-07 with triazole moiety was successfully achieved with an improved biological activity. Most of the compounds exhibited significant in vitro inhibitory activity against Mtb strain. Compound KC-11 was found to be the most potent against Mtb-DHFR with an IC50 of 6.79 µM and >18-fold selectivity towards Mtb-DHFR over h-DHFR. The present studies represent a well-designed successful attempt to achieve selective Mtb inhibition in micromolar ranges using structure- and ligand-based approaches. We anticipate these results will provide useful information for the further development of selective Mtb-DHFR inhibitors for the treatment of Mycobacterium tuberculosis.
Experimental
Conflict of interest
Acknowledgments We gratefully acknowledge the financial support by the CSIR SRF grant (Via letter No. 09/591(0145)/2016 EMR-I) to K.S. and Department of Biotechnology (DBT), Govt. of India, for providing Bioinformatics infrastructure facility (via letterno.AS/MP (RES.)/JH-5/2013). The authors are thankful to Dr. David R. Sherman and Reilling Liao for helping with enzymatic study and to Dr Vikas Kumar, SHUAT Allahabad, India for helping with sub-acute toxicity study.
Introduction Dihydrofolate reductase (DHFR) is an enzyme of fundamental importance in biochemistry and medicinal chemistry. It catalyzes the reduction of folic acid (FA) to tetrahydro-folic acid (THF) and couples with thymidylate synthase (TS) to catalyze the reductive methylation of dUMP to dTMP [1]. Inhibition of DHFR stops the synthesis of THF while inhibition of TS leads to “thymineless death” [2]. Therefore, DHFR inhibition has long been a striking goal for the development of chemotherapeutic agents against bacterial, parasitic infections as well as cancer [3].