title: Design and Synthesis of a Focused Library of Diamino Triazines as Potential Mycobacterium tuberculosis DHFR Inhibitors.
abstract: We report design of a series of 2,4-diamino triazines as Mycobacterium tuberculosis (Mtb) dihydrofolate reductase inhibitors. The synthesized compounds were evaluated against Mtb (H37Rv and Dormant stage H37Ra), their cytotoxicity was assessed (HepG2 and A549 cell lines), and selectivity toward Mtb was evaluated by testing against other bacterial strains. Some derivatives showed promising activity along with low cytotoxicity. The most potent compound in the whole cell assay (MIC 0.325 μM against H37Rv) showed selectivity in the enzyme assay and exhibited synergy with second line anti-TB agent p-amino salicylic acid. This study therefore provides promising molecules for further development as antituberculosis DHFR inhibitors.
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology , Matunga (E), Mumbai 400019, India.
authors.forename: Arundhati C
authors.initials: AC
authors.lastname: Lele
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology , Matunga (E), Mumbai 400019, India.
authors.forename: Archana
authors.initials: A
authors.lastname: Raju
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology , Matunga (E), Mumbai 400019, India.
authors.forename: Mihir P
authors.initials: MP
authors.lastname: Khambete
authors.affiliation: Radiation Medicine Center, Bhabha Atomic Research Centre, Tata Memorial Hospital Annex , Parel, Mumbai 400012, India.
authors.forename: M K
authors.initials: MK
authors.lastname: Ray
authors.affiliation: Radiation Medicine Center, Bhabha Atomic Research Centre, Tata Memorial Hospital Annex , Parel, Mumbai 400012, India.
authors.forename: M G R
authors.initials: MG
authors.lastname: Rajan
authors.affiliation: Combichem-Bioresource Center, Organic Chemistry Division, CSIR-National Chemical Laboratory , Pune 411008, India.
authors.forename: Manisha A
authors.initials: MA
authors.lastname: Arkile
authors.affiliation: Combichem-Bioresource Center, Organic Chemistry Division, CSIR-National Chemical Laboratory , Pune 411008, India.
authors.forename: Nandadeep J
authors.initials: NJ
authors.lastname: Jadhav
authors.affiliation: Combichem-Bioresource Center, Organic Chemistry Division, CSIR-National Chemical Laboratory , Pune 411008, India.
authors.forename: Dhiman
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology , Matunga (E), Mumbai 400019, India.
authors.forename: Mariam S
authors.initials: MS
authors.lastname: Degani
keywords: Diamino triazine; Mycobacterium tuberculosis; dihydrofolate reductase; enzyme assay; molecular modeling; selectivity; synergy