title: 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.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Al-Rashood
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt. Electronic address: ghadak25@yahoo.com.
authors.forename: Ghada S
authors.initials: GS
authors.lastname: Hassan
authors.affiliation: Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt.
authors.forename: Shahenda M
authors.initials: SM
authors.lastname: El-Messery
authors.affiliation: Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Mahmoud N
authors.initials: MN
authors.lastname: Nagi
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Technology (Microbiology), College of Pharmacy, Taibah University, Almadinah Almunawwarah 344, Saudi Arabia.
authors.forename: El-Sayed E
authors.initials: EE
authors.lastname: Habib
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Fatmah A M
authors.initials: FAM
authors.lastname: Al-Omary
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt. Electronic address: subbagh@yahoo.com.
authors.forename: Hussein I
authors.initials: HI
authors.lastname: El-Subbagh
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004926:Escherichia coli / Q000187:drug effects; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*
chemical_list: C000596732:2-(1,3,4-thiadiazolyl-thio)-quinazolin-4-one; C000596733:2-(4-methyl-thiazolyl-thio)-quinazolin-4-one; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D052999:Quinazolinones; D013762:Tetrahydrofolate Dehydrogenase
keywords: Antimicrobial testing; Antitumor screening; DHFR inhibition; Molecular modeling study; Quinazolin-4-ones; Synthesis