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  • The folate pathway plays an essential role

    2019-08-07

    The folate pathway plays an essential role in cell survival by generating 5, 10-methylene tetrahydrofolate as a one-carbon donor for the synthesis of deoxythymidine monophosphate (dTMP), purines, methionine and histidine. Disruption of this pathway leads to the critical deficiency of these key molecules, impaired DNA replication and ultimately cell death. Although DHFR is a validated drug target for bacterial and protozal infections, it is not currently invoked for TB therapy. Therefore, designing antifolate compounds that inhibit Mtb-DHFR activity and also the growth of Mtb may be a promising strategy for TB drug discovery and development.10, 11, 12 Methotrexate (MTX), pyrimethamine, and trimetrexate, clinically approved antifolates, are potent inhibitors of the Mtb-DHFR but they fail to inhibit the growth of Mtb, most likely due to an inability to permeate the lipid-rich cell wall. Compounds that have been reported as Mtb-DHFR inhibitors majorly belong to the triazine or pyrimidine class and are shown in Fig 114, 15, 16, 17, 18, 19. 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 Etoricoxib msds 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].