2. Academic Validation
  3. Nonclassical antifolates, part 5. Benzodiazepine analogs as a new class of DHFR inhibitors: synthesis, antitumor testing and molecular modeling study

Nonclassical antifolates, part 5. Benzodiazepine analogs as a new class of DHFR inhibitors: synthesis, antitumor testing and molecular modeling study

  • Eur J Med Chem. 2014 Mar 3:74:234-45. doi: 10.1016/j.ejmech.2014.01.004.
Hussein I El-Subbagh 1,  Ghada S Hassan 2,  Shahenda M El-Messery 3,  Sarah T Al-Rashood 4,  Fatmah A M Al-Omary 4,  Yasmin S Abulfadl 5,  Marwa I Shabayek 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University, 12311 Cairo, Egypt. Electronic address: subbagh@yahoo.com.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt.
  • 3 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt.
  • 4 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
  • 5 Department of Pharmacology (Biochemistry Section), Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University, 12311 Cairo, Egypt.
PMID: 24469112 DOI: 10.1016/j.ejmech.2014.01.004
Abstract

A new series of tetrahydro-quinazoline and tetrahydro-1H-dibenzo[b,e][1,4]diazepine analogs were synthesized and tested for their DHFR inhibition and in vitro antitumor activity. Compound 35 showed a remarkable DHFR inhibitory potency (IC₅₀, 0.004 μM) which is twenty fold more active than methotrexate (MTX). Compounds 17 and 23 proved to be fifteen fold more active than the known antitumor 5-FU, with MG-MID GI₅₀, TGI, and LC₅₀ values of 1.5, 46.8, 93.3 and 1.4, 17.4, 93.3 μM, respectively. Computer modeling studies allowed the identification that methoxy and methyl substituents, the π-system of the chalcone core, the nitrogen atoms, on the dibenzodiazepine ring as pharmacophoric features essential for activity. These MARK points could be used as template model for further future optimization.

Keywords

DHFR inhibition; Dibenzo[b,e][1,4]diazepines; Molecular modeling study; Synthesis; Tetrahydro-quinazolines.

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