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Preliminary Communication

Rational drug design, synthesis and biological evaluation of dihydrofolate reductase inhibitors as antituberculosis agents

    Nilesh R Tawari

    Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India

    ,
    Seema Bag

    Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India

    ,
    Archana Raju

    Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India

    ,
    Arundhati C Lele

    Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India

    ,
    Ranjeet Bairwa

    Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India

    ,
    Mukti Kanta Ray

    Radiation Medicine Center, Bhabha Atomic Research Centre, Tata Memorial Hospital Annex, Parel, Mumbai 400012, India

    ,
    MGR Rajan

    Radiation Medicine Center, Bhabha Atomic Research Centre, Tata Memorial Hospital Annex, Parel, Mumbai 400012, India

    ,
    Laxman U Nawale

    Combichem-Bioresource Center, Organic Chemistry Division, CSIR-National Chemical Laboratory, Pune 411008, India

    ,
    Dhiman Sarkar

    Combichem-Bioresource Center, Organic Chemistry Division, CSIR-National Chemical Laboratory, Pune 411008, India

    &
    Mariam S Degani

    *Author for correspondence:

    E-mail Address: msdegani@gmail.com

    Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India

    Published Online:https://doi.org/10.4155/fmc.15.48

    Background: A series of 2,4-diamino-s-triazines was designed, with potential for activity against Mycobacterium tuberculosis (Mtb) dihydrofolate reductase enzyme, on the basis of virtual screening results and structure-based drug design. Results: The compounds were evaluated against Mtb (H37Rv) and their cytotoxicity was assessed using VERO cell lines. Of particular note, two compounds were found to have the most promising antituberculosis activity (6b minimum inhibitory concentration: 1.76 μM and 6i minimum inhibitory concentration: 1.57 μM) along with low cytotoxicity (CC50: >300 μM). The enzyme assay results of these two indicated significant inhibition of Mtb dihydrofolate reductase along with selectivity. Selected derivatives were tested against dormant tubercle bacilli in vivo and ex vivo indicating potential inhibition. Conclusion: This study provides promising antituberculosis dihydrofolate reductase inhibitors that can act as potential leads for further development.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest.

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