ABSTRACT
Ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were synthesized in an attempt to develop potent anti-inflammatory agents. Structures of the synthesized compounds were elucidated by 1H NMR, 13C NMR, and HRMS. Most of the synthesized compounds showed pronounced anti-inflammatory effects at 100â¯mg/kg. In particular, compound 11b, which displayed the most potent anti-inflammatory activity of all of the compounds prepared, with 69.76% inhibition after intraperitoneal administration, was more potent than the reference drugs indomethacin and ibuprofen. The cytotoxicity of the compounds was also assessed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC50 >100⯵mol/L). Furthermore, molecular docking studies of the synthesized compounds were performed to rationalize the obtained biological results. Overall, the results indicate that compound 11b could be a therapeutic candidate for the treatment of inflammation.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Drug Design , Heterocyclic Compounds/chemistry , Nitrogen/chemistry , Triterpenes/chemistry , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Binding Sites , Cell Survival/drug effects , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Disease Models, Animal , Edema/chemically induced , Edema/drug therapy , Edema/pathology , HCT116 Cells , Humans , Mice , Molecular Docking Simulation , Protein Structure, Tertiary , Structure-Activity Relationship , Triterpenes/pharmacology , Triterpenes/therapeutic use , Ursolic AcidABSTRACT
Hypoxia-inducible factor-1α (HIF-1α), a key mediator in tumor metastasis and angiogenesis, is associated with poor patient prognosis and has been recognized as an important cancer drug target. In this work, four novel series of ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were designed, synthesized, and evaluated for anti-tumor activity as HIF-1α inhibitors. The majority of the compounds showed an excellent ability to inhibit the expression of HIF-1α. In particular, 11b inhibited HIF-1α transcriptional activity under hypoxic conditions with IC50=36.9µM. The cytotoxicity of these compounds was also assessed in human colon cancer cell HCT116 cells by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC50>100µmol/L), which was lower than that of ursolic acid (IC50=23.8µmol/L). The mechanism of action of the representative compound 11b was also investigated.
Subject(s)
Antineoplastic Agents/chemical synthesis , Drug Design , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Triterpenes/chemistry , Triterpenes/chemical synthesis , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints/drug effects , Cell Hypoxia , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Evaluation, Preclinical , HCT116 Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Inhibitory Concentration 50 , Structure-Activity Relationship , Transcription, Genetic/drug effects , Triterpenes/metabolism , Triterpenes/pharmacology , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Ursolic AcidABSTRACT
Three novel series of chalcone derivatives containing an aminoguanidine or acylhydrazone moiety were designed, synthesized and evaluated in terms of their antibacterial, antifungal and anti-inflammatory activities. Most of the synthesized compounds showed potent inhibitory activity towards various bacteria and one fungus with minimum inhibitory concentrations (MICs) ranging from 1 to 8µg/mL. Compared with our previously reported chalcone derivatives (MICs >64µg/mL), these compounds exhibited improved antibacterial activities (MICs=2µg/mL) against Gram-negative bacterial strains (Escherichia coli 1924 and 1356). Compounds 4f and 4h were found to be the most potent with an MIC value of 1µg/mL against the Gram-negative bacterial strains Salmonella typhimurium 1926 and the fungus Candida albicans 7535. In addition, compound 4f displayed the most potent anti-inflammatory activity of all of the compounds prepared in the current study with 92.45% inhibition after intraperitoneal administration, making it more potent than the reference drugs indomethacin and ibuprofen. The cytotoxic activity of the compound 4f was assessed in HeLa, Hep3B and L02 cells.
