2. Academic Validation
  3. Synthesis, biological evaluation and molecular modeling study of some new methoxylated 2-benzylthio-quinazoline-4(3H)-ones as nonclassical antifolates

Synthesis, biological evaluation and molecular modeling study of some new methoxylated 2-benzylthio-quinazoline-4(3H)-ones as nonclassical antifolates

  • Bioorg Med Chem Lett. 2016 Oct 1;26(19):4815-4823. doi: 10.1016/j.bmcl.2016.08.022.
Shahenda M El-Messery 1,  Ghada S Hassan 2,  Mahmoud N Nagi 3,  El-Sayed E Habib 4,  Sarah T Al-Rashood 5,  Hussein I El-Subbagh 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt. Electronic address: shahenda76@yahoo.com.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt.
  • 3 Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
  • 4 Department of Pharmaceutics and Pharmaceutical Technology (Microbiology), College of Pharmacy, Taibah University, Almadinah Almunawwarah 344, Saudi Arabia; Department of Microbiology, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt.
  • 5 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
  • 6 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University, 12311 Cairo, Egypt. Electronic address: subbagh@yahoo.com.
PMID: 27554444 DOI: 10.1016/j.bmcl.2016.08.022
Abstract

A new series of 2,3,6-substituted-quinazolin-4-ones was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 28 and 61 proved to be active DHFR inhibitors with IC50 0.02 and 0.01μM, respectively. Molecular modeling studies concluded that recognition with the key amino acid Phe34 is essential for binding and hence DHFR inhibition. Compounds 34, 56 and 66 showed broad spectrum antimicrobial activity comparable to Gentamicin and Ciprofloxacin. Compounds 40 and 64 showed broad spectrum antitumor activity toward several tumor cell lines and proved to be 10 fold more active than 5-FU, with GI50 MG-MID values of 2.2 and 2.4μM, respectively.

Keywords

Antimicrobial testing; Antitumor screening; DHFR inhibition; Molecular modeling study; Quinazolin-4-ones; Synthesis.

Figures