Synthesis, biological evaluation and molecular modeling study of new (1,2,4-triazole or 1,3,4-thiadiazole)-methylthio-derivatives of quinazolin-4(3H)-one as DHFR inhibitors

Yomna I El-Gazzar; Hanan H Georgey; Shahenda M El-Messery; Heba A Ewida; Ghada S Hassan; Marwa M Raafat; Menna A Ewida; Hussein I El-Subbagh

doi:10.1016/j.bioorg.2017.04.019

Synthesis, biological evaluation and molecular modeling study of new (1,2,4-triazole or 1,3,4-thiadiazole)-methylthio-derivatives of quinazolin-4(3H)-one as DHFR inhibitors

Bioorg Chem. 2017 Jun:72:282-292. doi: 10.1016/j.bioorg.2017.04.019. Epub 2017 May 4.

Authors

Yomna I El-Gazzar¹, Hanan H Georgey², Shahenda M El-Messery³, Heba A Ewida⁴, Ghada S Hassan⁵, Marwa M Raafat⁶, Menna A Ewida¹, Hussein I El-Subbagh⁷

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, 12311 Cairo, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, El-Kasr El-Eini Street, P.O. Box 11562, Cairo, Egypt.
³ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt.
⁴ Department of Pharmacology and Biochemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, 12311 Cairo, Egypt.
⁵ Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt.
⁶ Department of Microbiology, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, 12311 Cairo, Egypt.
⁷ Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt. Electronic address: [email protected].

PMID: 28499189
DOI: 10.1016/j.bioorg.2017.04.019

Abstract

A new series of 2-mercapto-quinazolin-4-one analogues was designed, synthesized and evaluated for their in vitro DHFR inhibition, antitumor and antimicrobial activity. Compound 17 proved to be the most active DHFR inhibitor with IC₅₀ value of 0.01μM, eight fold more active than methotrexate (MTX). Compounds 16 and 24 showed antitumor activity against human Caco2 colon and MCF-7 breast tumor cell lines with IC₅₀ values of 25.4 and 9.5μg/ml, respectively. Compounds 15, 20, 21 and 30 showed considerable activity against the Gram-positive bacteria Staphylococcus aureus while 24 and 30 proved active against Bacillus subtilis with a magnitude of potency comparable to the broad spectrum antibiotic Ciprofloxacin. Strong activity was observed for 13, 14, 19, 20 and 24 against Candida albicans and Aspergillus flavus. Compound 17 shared a similar molecular docking mode with MTX and made a critical hydrogen bond and arene-arene interactions via Ala9 and Phe34 amino acid residues, respectively.

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

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Folic Acid Antagonists / chemical synthesis
Folic Acid Antagonists / chemistry
Folic Acid Antagonists / pharmacology*
Humans
Models, Molecular
Molecular Structure
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology*
Structure-Activity Relationship
Tetrahydrofolate Dehydrogenase / metabolism*

Substances

Antineoplastic Agents
Folic Acid Antagonists
Quinazolines
Tetrahydrofolate Dehydrogenase