title: Rational drug design, synthesis and biological evaluation of dihydrofolate reductase inhibitors as antituberculosis agents.
abstract: 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.
  
  
  CONCLUSIONS
  This study provides promising antituberculosis dihydrofolate reductase inhibitors that can act as potential leads for further development.
authors.affiliation: Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India.
authors.forename: Nilesh R
authors.initials: NR
authors.lastname: Tawari
authors.affiliation: Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India.
authors.forename: Seema
authors.initials: S
authors.lastname: Bag
authors.affiliation: Department of Pharmaceutical Sciences & 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 & 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 & Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India.
authors.forename: Ranjeet
authors.initials: R
authors.lastname: Bairwa
authors.affiliation: Radiation Medicine Center, Bhabha Atomic Research Centre, Tata Memorial Hospital Annex, Parel, Mumbai 400012, India.
authors.forename: Mukti Kanta
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: Laxman U
authors.initials: LU
authors.lastname: Nawale
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 & Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India.
authors.forename: Mariam S
authors.initials: MS
authors.lastname: Degani
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase