ABSTRACT
Two series of 2-phenyl-4(3H) quinazolinone derivatives have been synthesized. Most of the tested quinazolinone derivatives showed considerable potent anti-inflammatory and analgesic activity of superior GIT safety profile in experimental rats in comparing to indomethacin as reference drug. Compounds VIa, VIb were the most potent anti-inflammatory in experimental rats in comparing to indomethacin as reference drug. Docking study into COX-2 has been made for derivatives of anti-inflammatory activity.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Carrageenan , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Drug Design , Edema/chemically induced , Edema/prevention & control , Female , Hot Temperature , Indomethacin/chemistry , Male , Mice , Models, Molecular , Pain Measurement/drug effects , Quinazolines/chemistry , Rats , Reaction Time/drug effects , Stomach Ulcer/chemically induced , Structure-Activity RelationshipABSTRACT
Starting from 4-(6,8-dibromo-2-phenyl-4-oxo-(4H)-quinazolin-3-yl)-benzoic acid ethyl ester (II) and its acid hydrazide III, a new series of Schiff bases IV and their cyclized products, thiazolidinones V, oxadiazole VIII, pyrazoles X-XII, pyrroles XIII-XV and other related products were synthesized. These compounds were screened for their anti-bacterial activity against Gram-positive bacteria (Staphylococcus aureus, Legionella monocytogenes and Bacillus cereus) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Salmonella typhimurium) and anti-fungal activity (Candida albicans and Aspergillus flavus) using paper disc diffusion technique. The minimum inhibitory concentrations (MICs) of the compounds were also determined by agar streak dilution method. Among the synthesized compounds 2-(4-(2-phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-ethylamido benzoic acid hydrazide VIIa was found to exhibits the most potent in vitro anti-microbial activity with the MICs of 1.56, 3.125, 1.56, 25, 25 and 25 microg/ml against E. coli, S. typhimurium, L. monocytogenes, S. aureus, P. aeruginosa, and B. cereus respectively. Compound 2-(4-(2-phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-methyl thioamido benzoic acid hydrazide VIIc was found to exhibit the most potent in vitro anti-fungal activity with MICs 0.78 and 0.097 microg/ml against C. albicans and A. flavus.
Subject(s)
Bacteria/drug effects , Drug Design , Fungi/drug effects , Quinazolinones/chemistry , Quinazolinones/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antifungal Agents/toxicity , Drug-Related Side Effects and Adverse Reactions , Microbial Sensitivity Tests , Quinazolinones/chemical synthesis , Quinazolinones/toxicityABSTRACT
A new series of the title compounds incorporated into diverse N and O heterocyclic moieties of pharmacoavailability as anti-inflammatory and analgesic agents, were synthesized starting with 6,8-dibromo-2-phenyl-4H-3,1-benzoxazin-4-one (I) by its fusion with p-aminoacetophenone to give the new intermediate compound, 6,8-dibromo-2-phenyl-3-(4-acetylphenyl)-4(3H)-quinazolinone (II). The one pot reaction of II with the appropriate aromatic aldehydes and anhyd. ammonium acetate in the presence of either ethyl cyanoacetate or malononitrile afforded the corresponding 2(1H)-pyridones III or 2(1H)-iminopyridines IV, respectively, while its reaction with malononitrile and aromatic aldehydes in piperidine gave 2-aminopyrans V. Also, reaction of the acetyl derivative II with aromatic aldehydes afforded the corresponding 1,3-propen-1-one derivatives VI which underwent cyclization with hydrazine to give the corresponding pyrazolines VII and with urea and/or thiourea to give the corresponding tetrahydropyrimidin-2-ones and/or tetrahydropyrimidin-2-thiones VIII. Some representative examples of the new compounds showed promising anti-inflammatory and analgesic activities in experimental animals.
Subject(s)
Analgesics/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Quinazolinones/chemical synthesis , Stomach Neoplasms/chemically induced , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Female , Male , Mice , Quinazolinones/pharmacology , Quinazolinones/toxicity , RatsABSTRACT
A new series of the title compounds incorporated into diverse N and O heterocyclic moieties of pharmacoavailability as anti-inflammatory or analgesic agents, were synthesized starting with 6-bromo-2-phenyl-4H-3,1-benzoxazin-4-one (I) by its fusion with p-aminoacetophenone to give the intermediate compound, 6-bromo-2-phenyl-3-(4-acetylphenyl)-4(3H)quinazolinone (II). The one pot reaction of II with the appropriate aromatic aldehydes and anhyd. ammonium acetate in the presence of either ethyl cyanoacetate or malononitrile afforded the corresponding 2(1H)-pyridone derivatives III or 2(1H)- iminopyridine derivatives IV, respectively, while its reaction with malononitrile and aromatic aldehydes in piperdine gave the 2-aminopyrans V. Also reaction of the acetyl derivative II with different aromatic aldehydes afforded the corresponding 1,3-propen-1-one derivatives VI which underwent cyclization with hydrazines to give the corresponding pyrazoline derivatives VII and with urea or thiourea to give the pyrimidones or pyrimidinethiones VIII. Some representative examples of the new compounds showed promising anti-inflammatory and analgesic activities in experimental animals.
