Non-classical antifolates. Part 2: Synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 8; pp. 2849 - 2863
• Main Authors: Al-Omary, Fatmah A.M., Abou-zeid, Laila A., Nagi, Mahmoud N., Habib, El-Sayed E., Abdel-Aziz, Alaa A.-M., El-Azab, Adel S., Abdel-Hamide, Sami G., Al-Omar, Mohamed A., Al-Obaid, Abdulrahman M., El-Subbagh, Hussein I.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.04.2010; Elsevier
• Subjects: Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimicrobial activity; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor screening; Biological and medical sciences; Cell Line, Tumor; DHFR inhibition; Drug Screening Assays, Antitumor; Folic Acid Antagonists - chemical synthesis; Folic Acid Antagonists - chemistry; Folic Acid Antagonists - pharmacology; General aspects; Humans; Hydrophobic and Hydrophilic Interactions; Medical sciences; Molecular Dynamics Simulation; Molecular modeling study; Pharmacology. Drug treatments; Quinazolin-4-ones; Quinazolinones - chemical synthesis; Quinazolinones - chemistry; Quinazolinones - pharmacology; Static Electricity; Structure-Activity Relationship; Synthesis; Tetrahydrofolate Dehydrogenase - chemistry; Tetrahydrofolate Dehydrogenase - metabolism; Antitumor screening; Quinazolin-4-ones; Antimicrobial activity; Molecular modeling study; Synthesis; DHFR inhibition; Pseudomonadales; Antineoplastic agent; Bacillus subtilis; Quinazoline derivatives; Escherichia coli; Molecular dynamics method; Bacillaceae; Modeling; Antimicrobial agent; Antifolate; Bacillales; Structure activity relation; Molecular model; Bacteria; Micrococcales; Pseudomonadaceae; Pseudomonas aeruginosa; Micrococcaceae; Dihydrofolate reductase; Inhibition; Chemical synthesis; Staphylococcus aureus; Enterobacteriaceae; Enzyme; Theoretical study; In vitro; Micrococcus luteus; Screening; Antimetabolic; Carboxamide; Oxidoreductases; Aromatic amine
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.03.019

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 IC 50 range of 0.4–1.0 μM. Compound 18 showed broad-spectrum antimicrobial activity comparable to the known antibiotic gentamicin. Compounds 34 and 36 showed antitumor activity at GI 50 (MG-MID) concentrations of 11.2, and 24.2 μM, 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 π-systems in regard to the quinazoline nucleus proved critical for biological activity.