ABSTRACT
AIM: Discovery of novel series of colchicine binding site inhibitors (CBSIs). MATERIALS & METHODS: Isoxazoline 3a-d, pyrazoline 4a-b, 7a-f and 8a-f, cyclohexenone 9a-b and 10a-b or pyridine derivatives 11a-b were synthesized and evaluated for their inhibition of tubulin polymerization and cytotoxicity. Most of the compounds displayed potent to moderate antitumor activity against leukemia SR cell line.7c, 7e and 11a were more potent than colchicine with IC50 of 0.09, 0.05 and 0.06 µM, and percentage inhibition in tubulin polymerization of 95.2, 96.0 and 96.3%, respectively. Compounds 7c and 11a showed cell-cycle arrest at G2/M phase and induced apoptosis and were able to bind the colchicine binding site of tubulin with comparable affinity to colchicine. Docking study showed that these compounds may interact with tubulin exploiting a binding cavity not commonly reported in the binding of CBSI. CONCLUSION: Compounds 7c and 11a may be considered as promising CBSI based on their excellent activity and favorable drug likeness profile.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Furans/chemistry , Furans/pharmacology , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Antineoplastic Agents/chemical synthesis , Binding Sites/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Colchicine/metabolism , Drug Design , Drug Screening Assays, Antitumor , Furans/chemical synthesis , Halogenation , Humans , Leukemia/drug therapy , Leukemia/metabolism , Leukemia/pathology , Molecular Docking Simulation , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Polymerization/drug effects , Tubulin/chemistry , Tubulin/metabolism , Tubulin Modulators/chemical synthesisABSTRACT
AIM: Search for new anti-inflammatory agents with higher efficacy and lower toxicity is an urgent demand in drug discovery era. METHODOLOGY: Different pyrazoline derivatives 4a,b, 5a,b, 6a-h and 7a-f were prepared from the condensation reactions of 1,5-bis(5-methylfuran/thiophen-2-yl)penta-1,4-dien-3-ones 3a,b with different hydrazine derivatives. All compounds were screened for their anti-inflammatory activity using the carrageenan-induced paw edema method in rats and TNF-α inhibition assay. RESULTS: Many compounds revealed promising anti-inflammatory activity relative to indomethacin especially compounds 4a, 5a, 5b, 6b, 6d, 6f and 7b. They were safe to the gastric mucosa and did not cause toxicity up to tenfolds the anti-inflammatory dose, in addition, all compounds inhibited TNF-α with IC50 values of 1.7-100 nM.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Edema/drug therapy , Pyrazoles/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Carrageenan , Dose-Response Relationship, Drug , Edema/chemically induced , Mice , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolismABSTRACT
A series of new 9-glycosyl-4,9-dihydropyrano[3,4-b]indole-1(3H)-ones 3 was synthesized in moderate to low yields. 4,9-Dihydropyrano[3,4-b]indole-1(3H)-ones (1) were coupled with different acetobromoglycopyranoses 2 in refluxing toluene in the presence of silver oxide to afford one coupling product of the respective N-glycosides. α-L-Arabinopyranosides 3j and 3m were the most active glycosides among the tested compounds against certain Gram positive and Gram negative bacterial strains.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Indoles/chemistry , Indoles/pharmacology , Pyrans/chemistry , Pyrans/pharmacology , Anti-Bacterial Agents/chemical synthesis , Bacteria/drug effects , Bacterial Infections/drug therapy , Humans , Indoles/chemical synthesis , Microbial Sensitivity Tests , Pyrans/chemical synthesisABSTRACT
A new isatin ribonucleoside (3) was synthesized in a good yield by trimethylsilyl trifluoromethanesulfonate (TMSOTf) catalyzed coupling reaction between the silylated nitrogenated base of 1H-Indole-2,3-dione (1) and 1,2,3,5-tetra-O-acetyl-beta-D-ribfuranose (2). Thiosemicarbazides 4a-e were utilized by the prepared ribonucleoside (3) to give new series of 1H-indole-2,3-dione-3-thiosemicarbazone ribonucleosides 5a-e. All compounds tested as antibacterial agents showed slight inhibitory activity against the selected bacterial strains.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Ribonucleosides/chemical synthesis , Ribonucleosides/pharmacology , Thiosemicarbazones/chemical synthesis , Thiosemicarbazones/pharmacology , Alkylation/drug effects , Anti-Bacterial Agents/chemistry , Isomerism , Microbial Sensitivity Tests , Ribonucleosides/chemistry , Thiosemicarbazones/chemistryABSTRACT
A variety of tropane derivatives 14a-g were prepared via the reaction of the alcohol analogs 12a and 12b with substituted fluorobenzenes 13a-f. The prepared compounds were tested for their activity and selectivity toward the norepinephrine transporter (NET) and serotonin transporter (SERT) using yohimbine-induced mortality and 5-hydroxytryptophan-induced neurotoxicity in mice, respectively. All the tested compounds were found to be NE and 5-HT reuptake inhibitors except 14d which exhibited selective 5-HT reuptake inhibition activity.
