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  • In our current work we have undertaken liquid phase

    2019-11-14

    In our current work, we have undertaken liquid phase combinatorial synthesis methods for the synthesis of 1,2,5-trisubstituted benzimidazole derivatives as hDHODH inhibitors. Synthesised Nile Red australia were also screened by molecular docking studies over the reported hDHODH structure. The synthesised molecules were characterised by FT-IR, MASS and NMR analysis and the purity of compounds was evaluated by HPLC. The pharmacological activity of compounds was evaluated by in vitro hDHODH enzyme inhibition assays method and compared the activity of synthesised molecules with the standard brequinar [9], [11].
    Material and methods
    Results and discussion
    Conclusion The present work demonstrated liquid phase combinatorial synthesis, structure elucidations, docking analysis, and in vitro human DHODH enzyme inhibition activity of 1,2,5-trisubstituted benzimidazole derivatives. Liquid phase combinatorial synthesis approach was used to synthesise and evaluated a series of 1,2,5-trisubstituted benzimidazole derivatives in good yields. Compound 7d, 7e, 8d, 8e and 8i showed good human DHODH enzyme inhibition activity, whereas other compounds showed moderate to significant in vitro human DHODH enzyme inhibition. The obtained enzyme inhibition results are comparative to the molecular docking studies. The compounds which demonstrated good docking score also exhibited good enzyme inhibition activity. Thus, the in silico studies and the in vitro assay can be directly correlated and further development of this series of molecules can be carried out for optimisation of lead molecules identified in this study. The potency and selectivity of these compounds make them valid leads as human DHODH inhibitors for the development of improved drug-like candidates.
    Acknowledgments All of the authors are thankful to SERB project Government of India, Department of Science and Technology (DST) India for financial support under Project No.: SB/S1/OC-61/2013. This research work is a part of PhD thesis of Nikum Sitwala, Institute of Pharmacy, Nirma University. All authors are grateful to Nirma University for providing necessary facilities to carry out the research work.
    Malaria is one of the main infectious diseases in the world, with an estimated 212 million cases in 2015, centred to a great extent on the countries in central Africa and south east Asia. The numbers are even starker when one considers these cases led to an estimated 429,000 deaths and that approximately 70% of these deaths were of children under five years old. Malaria is considered a ‘preventable’ disease, largely because of the use of chemotherapeutic agents, however widespread drug resistance has rendered these agents ineffective in many regions of the world. This problem has led to much effort being expended into validating novel drug targets, as well as discovering small molecule enzyme inhibitors to act as leads for development of new antimalarial drugs. One such target which has attracted recent attention is dihydroorotate dehydrogenase (DHODH), a key enzyme in the obligate pyrimidine pathway for uridine monophosphate (UMP) biosynthesis. Early work aimed towards the discovery of DHODH inhibitors focussed on modification of the human DHODH (DHODH) inhibitors known at the time, such as brequinar (). This work was naturally followed by high throughput screening and design approaches. During the progress of this work, co-crystallisation and docking, experiments revealed that the inhibitors discovered targeted the ubiquinone binding channel, and also revealed important features for the design of selective and potent inhibitors. Firstly amino acid residues H185 and/or R265, at the head of the ubiquinone-binding channel, were found to be essential for hydrogen bonding interactions with the inhibitors. The ubiquinone channel also contained a hydrophobic region which contributes to the binding of the more potent inhibitors reported. Indeed many of the inhibitors reported to date, , , , , , reveal broadly this amphiphilic nature, and possess a polar ‘head group’ and hydrophobic ‘tail’. Triazolopyrimidine DSM265 () is currently the most advanced DHODH inhibitor, and Phase 1 clinical trials for this candidate have recently been reported.