Nonclassical antifolates, part 3: synthesis, biological evaluation and molecular modeling study of some new 2-heteroarylthio-quinazolin-4-ones

Fatmah A M Al-Omary; Ghada S Hassan; Shahenda M El-Messery; Mahmoud N Nagi; El-Sayed E Habib; Hussein I El-Subbagh

doi:10.1016/j.ejmech.2012.12.061

Nonclassical antifolates, part 3: synthesis, biological evaluation and molecular modeling study of some new 2-heteroarylthio-quinazolin-4-ones

Eur J Med Chem. 2013 May:63:33-45. doi: 10.1016/j.ejmech.2012.12.061. Epub 2013 Feb 13.

Authors

Fatmah A M Al-Omary¹, Ghada S Hassan, Shahenda M El-Messery, Mahmoud N Nagi, El-Sayed E Habib, Hussein I El-Subbagh

Affiliation

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

PMID: 23454532
DOI: 10.1016/j.ejmech.2012.12.061

Abstract

A new series of 2-heteroarylthio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 21, 25, and 39 proved to be active DHFR inhibitors with IC50 range of 0.3-0.8 μM. Compounds 25, 28, 33, 35 and 36 showed broad spectrum antimicrobial activity comparable to the known antibiotic gentamicin. Compound 29 showed broad spectrum antitumor activity toward several tumor cell lines with GI values range of 25.8-41.2%. Molecular modeling studies concluded that recognition with key amino acid Arg38 and Lys31 are essential for binding and biological activities. Flexible alignment; electrostatic and hydrophobic mappings revealed that the obtained model could be useful for the development of new DHFR inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Infective Agents / chemical synthesis
Anti-Infective Agents / chemistry
Anti-Infective Agents / pharmacology
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Biocatalysis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Folic Acid Antagonists / chemical synthesis
Folic Acid Antagonists / chemistry*
Folic Acid Antagonists / pharmacology
Gram-Negative Bacteria / drug effects
Gram-Positive Bacteria / drug effects
HL-60 Cells
Humans
MCF-7 Cells
Microbial Sensitivity Tests
Models, Chemical
Models, Molecular*
Molecular Dynamics Simulation
Molecular Structure
Protein Structure, Tertiary
Quinazolines / chemical synthesis
Quinazolines / chemistry*
Quinazolines / pharmacology
Quinazolinones / chemical synthesis
Quinazolinones / chemistry*
Quinazolinones / pharmacology
Structure-Activity Relationship
Tetrahydrofolate Dehydrogenase / metabolism

Substances

Anti-Infective Agents
Antineoplastic Agents
Folic Acid Antagonists
Quinazolines
Quinazolinones
Tetrahydrofolate Dehydrogenase