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Nonclassical antifolates, part 3: synthesis, biological evaluation and molecular modeling study of some new 2-heteroarylthio-quinazolin-4-ones
- Source :
- European journal of medicinal chemistry. 63
- Publication Year :
- 2012
-
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.
- Subjects :
- Models, Molecular
Molecular model
Stereochemistry
Antineoplastic Agents
HL-60 Cells
Microbial Sensitivity Tests
Molecular Dynamics Simulation
Gram-Positive Bacteria
Structure-Activity Relationship
Protein structure
Anti-Infective Agents
Cell Line, Tumor
parasitic diseases
Drug Discovery
Gram-Negative Bacteria
Structure–activity relationship
Molecule
Humans
IC50
Cell Proliferation
Quinazolinones
Pharmacology
chemistry.chemical_classification
Molecular Structure
Organic Chemistry
General Medicine
Antimicrobial
Combinatorial chemistry
Amino acid
Protein Structure, Tertiary
Tetrahydrofolate Dehydrogenase
chemistry
Models, Chemical
Cell culture
Biocatalysis
MCF-7 Cells
Quinazolines
Folic Acid Antagonists
Subjects
Details
- ISSN :
- 17683254
- Volume :
- 63
- Database :
- OpenAIRE
- Journal :
- European journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....0117671a8c6b15eae5a412f3fd27bb0a