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Non-classical antifolates. Part 2: Synthesis, biological evaluation, and molecular modeling study of
Bioorganic & Medicinal Chemistry 18 (2010) 2849–2863
Non-classical antifolates. Part 2: Synthesis, biological evaluation, and molecular modeling study of some new
2,6-substituted-quinazolin-4-ones
Fatmah A. M. Al-Omary, Laila A. Abou-zeid, Mahmoud N. Nagi, El-Sayed E. Habib, Alaa A.-M. Abdel-Aziz, Adel S. El-Azab, Sami G. Abdel-Hamide, Mohamed A. Al-Omar, Abdulrahman M. Al-Obaid, Hussein I. El-Subbagh.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University,
Riyadh 11451, Saudi Arabia
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, University of
Mansoura, Mansoura 35516, Egypt.
Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451,
Saudi Arabia
Department of Pharmaceutical Microbiology, Faculty of Pharmacy, University of Mansoura,
Mansoura 35516, Egypt
A new series of 2,6-substituted-quinazolin-4-ones was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 22, 33–37, 39–43, and 45 proved to be active DHFR inhibitors with IC50 range of 0.4–1.0 uM. Compound 18 showed broad-spectrum antimicrobial activity comparable to the known antibiotic gentamicin. Compounds 34 and 36 showed antitumor activity at GI50 (MG-MID) concentrations of 11.2, and 24.2 uM, respectively. Molecular modeling study including flexible alignment; electrostatic, hydrophobic mappings; and pharmacophore prediction were performed. A main featured pharmacophore model was developed which justifies the importance of the main pharmacophoric groups as well as of their relative distances. The substitution pattern and spatial considerations of the p-systems in regard to the quinazoline nucleus proved critical for biological activity.
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