ABSTRACT
Antibiotic-resistant bacteria continue to play an important role in human health and disease. Inventive strategies are necessary to develop new therapeutic leads to challenge drug-resistance problems. From this perception, new quinoline hybrids bearing bioactive pharmacophores were synthesized. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against nine bacterial pathogenic strains. The results revealed that most compounds exhibited good antibacterial activities. Seven compounds (2b, 3b, 4, 6, 8b, and 9c,d) displayed enhanced activity against methicillin-resistant Staphylococcus aureus compared to ampicillin. These compounds were subjected to an in vitro S. aureus DNA gyrase ATPase inhibition study, which revealed that compounds 8b, 9c, and 9d showed the highest inhibitory activity with IC50 values of 1.89, 2.73, and 2.14 µM, respectively, comparable to novobiocin (IC50 , 1.636 µM). Compounds 2a-c, 3a, 7c, 9c,d, and 10a,b revealed half the potency of levofloxacin in inhibiting the growth of Pseudomonas aeruginosa. As an attempt to rationalize the observed antibacterial activity for the most active compounds 8b, 9c, and 9d, molecular docking in the ATP binding site of S. aureus gyrase B was performed using Glide. Such compounds could be considered as promising scaffolds for the development of new potent antibacterial agents.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Methicillin-Resistant Staphylococcus aureus/drug effects , Quinolines/chemical synthesis , Topoisomerase II Inhibitors/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Binding Sites , Drug Design , Humans , Inhibitory Concentration 50 , Methicillin-Resistant Staphylococcus aureus/enzymology , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Protein Binding , Pseudomonas aeruginosa/drug effects , Quinolines/chemistry , Quinolines/pharmacology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacologyABSTRACT
New quinoline compounds comprising pyrazole scaffold through different amide linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory activity. Eight compounds (5c, 11b,c, 12c, 14a,b, 20a and 21a) were found to exhibit promising anti-inflammatory profiles in acute and sub-acute inflammatory models. They were screened for their ulcerogenic activity and none of them showed significant ulcerogenic activity comparable to the reference drug celecoxib and are well tolerated by experimental animals with high safety margin (ALD50â¯>â¯0.3â¯g/kg). Compounds 5c, 11b,c, 12c, 14a,b, 20a and 21a showed significant in vitro LOX inhibitory activity higher than that of zileuton. In vitro COX-1/COX-2 inhibition study revealed that compounds 12c, 14a,b and 20a showed higher selectivity towards COX-2 than COX-1. Among the tested compounds, 12c, 14a and 14b showed the highest inhibitory activity against COX-2 with an IC50 values of 0.1, 0.11 and 0.11⯵M respectively. The docking experiments attempted to postulate the binding mode for the most active compounds in the binding site of COX-2 enzymes and confirmed the high selectivity binding towards COX-2 enzyme over COX-1.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Ulcer Agents/pharmacology , Cyclooxygenase Inhibitors/pharmacology , Lipoxygenase Inhibitors/pharmacology , Molecular Docking Simulation , Quinolines/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Ulcer Agents/chemical synthesis , Anti-Ulcer Agents/chemistry , Arachidonate 5-Lipoxygenase/metabolism , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/chemistry , Dose-Response Relationship, Drug , Edema/chemically induced , Edema/drug therapy , Formaldehyde , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/chemistry , Male , Molecular Structure , Quinolines/chemical synthesis , Quinolines/chemistry , Rats , Glycine max/enzymology , Stomach Ulcer/chemically induced , Stomach Ulcer/drug therapy , Structure-Activity RelationshipABSTRACT
A series of new sulfanyltriazolylnaphthalenols (10a-f and 13a-f) and sulfanyltriazolylnaphthalene-1,4-diones (14a-f) were synthesized and evaluated against a panel of cancer cell lines. Among the tested compounds, 10b and 10d showed the best anti-proliferative activity with GI50 values ranging from 2.72 to 10 and 3.13 to 13.1 µM, respectively, in several of the tumor cell lines tested. Compound 10d is highly selective toward leukemia cell lines and can be regarded as a good model for the development of new anti-leukemic agents.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Naphthalenes/chemical synthesis , Naphthalenes/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Naphthalenes/chemistry , Structure-Activity RelationshipABSTRACT
A series of new oxadiazoline-substituted naphthalenyl acetates 3a-e and oxadiazoline-substituted 4-methoxynaphthalenyl acetates 7b-e were synthesized and tested by the National Cancer Institute (NCI) for their in vitro anticancer activity. The two derivatives bearing acetoxy groups at the 1 and 3 positions of the phenyl ring 3c and 7c were the most active showing significant anticancer activity against all tested cancer cell lines, with GI50 values ranging from 0.175 to 3.91 µM, and 0.306-11.7 µM, respectively. The selectivity of compound 3c was greater for non-solid tumor cell lines. Computational prediction of molecular and pharmacokinetic properties revealed that both compounds are safe and compound 7c had a good drug-likeness score.