Synthesis, biological evaluation and molecular modeling study of 2-(1,3,4-thiadiazolyl-thio and 4-methyl-thiazolyl-thio)-quinazolin-4-ones as a new class of DHFR inhibitors

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

doi:10.1016/j.bmcl.2014.07.070

Synthesis, biological evaluation and molecular modeling study of 2-(1,3,4-thiadiazolyl-thio and 4-methyl-thiazolyl-thio)-quinazolin-4-ones as a new class of DHFR inhibitors

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4557-4567. doi: 10.1016/j.bmcl.2014.07.070. Epub 2014 Aug 4.

Authors

Sarah T Al-Rashood¹, Ghada S Hassan², Shahenda M El-Messery³, Mahmoud N Nagi⁴, El-Sayed E Habib⁵, Fatmah A M Al-Omary¹, Hussein I El-Subbagh⁶

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
² Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt. Electronic address: ghadak25@yahoo.com.
³ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt.
⁴ Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
⁵ Department of Pharmaceutics and Pharmaceutical Technology (Microbiology), College of Pharmacy, Taibah University, Almadinah Almunawwarah 344, Saudi Arabia.
⁶ Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt. Electronic address: subbagh@yahoo.com.

PMID: 25139568
DOI: 10.1016/j.bmcl.2014.07.070

Abstract

A new series of 2-(1,3,4-thiadiazolyl- or 4-methyl-thiazolyl)thio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 29, 34, and 39 proved to be the most active DHFR inhibitors with IC50 values range of 0.1-0.6 μM. Compounds 28, 31 and 33 showed remarkable broad-spectrum antimicrobial activity comparable to the known antibiotic Gentamicin. Compounds 26, 33, 39, 43, 44, 50, 55 and 63 showed broad spectrum antitumor activity with GI values range of 10.1-100%. Molecular modeling study concluded that recognition with key amino acid Glu30, Phe31 and Phe34 is essential for binding. ADMET properties prediction of the active compounds suggested that compounds 29 and 34 could be orally absorbed with diminished toxicity.

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

Publication types

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

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Antifungal Agents / chemical synthesis
Antifungal Agents / chemistry
Antifungal Agents / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Bacillus subtilis / drug effects
Candida albicans / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Escherichia coli / drug effects
Folic Acid Antagonists / chemical synthesis
Folic Acid Antagonists / chemistry
Folic Acid Antagonists / pharmacology*
Humans
Models, Molecular
Molecular Structure
Quinazolinones / chemical synthesis
Quinazolinones / chemistry
Quinazolinones / pharmacology*
Staphylococcus aureus / drug effects
Structure-Activity Relationship
Tetrahydrofolate Dehydrogenase / metabolism*

Substances

2-(1,3,4-thiadiazolyl-thio)-quinazolin-4-one
2-(4-methyl-thiazolyl-thio)-quinazolin-4-one
Anti-Bacterial Agents
Antifungal Agents
Antineoplastic Agents
Folic Acid Antagonists
Quinazolinones
Tetrahydrofolate Dehydrogenase