ABSTRACT
The high potential of quinoline containing natural products and their derivatives in medicinal chemistry led us to discover novel series of 25 compounds for the development of new antileishmanial agents. A series of triazolyl 2-methyl-4-phenylquinoline-3-carboxylate derivatives has been synthesized via click chemistry inspired molecular hybridization approach and evaluated against Leishmania donovani. Most of the screened derivatives exhibited significant in vitro anti-leishmanial activity against promastigote (IC50 ranging from 2.43 to 45.75⯵M) and intracellular amastigotes (IC50 ranging from 7.06 to 34.9⯵M) than the control, miltefosine (IC50â¯=â¯8.4⯵M), with less cytotoxicity in comparison to the standard drugs. Overall results revealed that prototype signify a new structural lead for antileishmanial chemotherapy.
Subject(s)
Antiprotozoal Agents/pharmacology , Leishmania donovani/drug effects , Quinolines/pharmacology , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Dose-Response Relationship, Drug , Molecular Structure , Parasitic Sensitivity Tests , Quinolines/chemical synthesis , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
In the search for effective multifunctional agents for the treatment of Alzheimer's disease (AD), a series of novel hybrids incorporating benzofuran and chalcone fragments were designed and synthesized. These hybrids were screened by using a transgenic Caenorhabditis elegans model that expresses the human ß-amyloid (Aß) peptide. Among the hybrids investigated, (E)-3-(7-methyl-2-(4-methylbenzoyl)benzofuran-5-yl)-1-phenylprop-2-en-1-one (4 f), (E)-3-(2-benzoyl-7-methylbenzofuran-5-yl)-1-phenylprop-2-en-1-one (4 i), and (E)-3-(2-benzoyl-7-methylbenzofuran-5-yl)-1-(thiophen-2-yl)prop-2-en-1-one (4 m) significantly decreased Aß aggregation and increased acetylcholine (ACh) levels along with the overall availability of ACh at the synaptic junction. These compounds were also found to decrease acetylcholinesterase (AChE) levels, reduce oxidative stress in the worms, lower lipid content, and to provide protection against chemically induced cholinergic neurodegeneration. Overall, the multifunctional effects of these hybrids qualify them as potential drug leads for further development in AD therapy.
Subject(s)
Antioxidants/chemical synthesis , Benzofurans/chemistry , Chalcone/chemistry , Chalcones/chemistry , Thiophenes/chemistry , Acetylcholine/metabolism , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Animals , Animals, Genetically Modified/metabolism , Antioxidants/pharmacology , Antioxidants/therapeutic use , Benzofurans/pharmacology , Benzofurans/therapeutic use , Binding Sites , Caenorhabditis elegans/metabolism , Chalcones/pharmacology , Chalcones/therapeutic use , Crystallography, X-Ray , Disease Models, Animal , Humans , Microscopy, Fluorescence , Molecular Conformation , Molecular Docking Simulation , Oxidative Stress/drug effects , Protein Structure, Tertiary , Structure-Activity Relationship , Thiophenes/pharmacology , Thiophenes/therapeutic useABSTRACT
A series of novel indole-chalcone fibrates were synthesized and their hypolipidemic activity was evaluated in triton WR-1339 induced hyperlipidemic rat model. Preliminary studies indicated that the hybrids 19, 24 and 29 exhibited potent in vitro antioxidant and significant in vivo antidyslipidemic effects. Our results suggest that these new hybrid architectures may serve as promising leads for the development of next generation lipid lowering agents.
Subject(s)
Antioxidants/pharmacology , Chalcone/pharmacology , Drug Design , Hyperlipidemias/drug therapy , Hypolipidemic Agents/pharmacology , Indoles/pharmacology , Animals , Antioxidants/chemical synthesis , Antioxidants/chemistry , Chalcone/chemistry , Disease Models, Animal , Hyperlipidemias/chemically induced , Hypolipidemic Agents/chemical synthesis , Hypolipidemic Agents/chemistry , Indoles/chemistry , Lipoproteins/blood , Lipoproteins, HDL/blood , Lipoproteins, HDL/metabolism , Lipoproteins, LDL/blood , Lipoproteins, LDL/metabolism , Male , Molecular Structure , Polyethylene Glycols/administration & dosage , RatsABSTRACT
A novel series of amide based fibrates were synthesized and evaluated for antidyslipidemic activity in triton induced hyperlipidemic rats. Interestingly, the compound 13 produced striking reduction in serum levels of total cholesterol (TC), phospholipids (PL) and triglycerides (TG). In addition, it exhibited improved lipoprotein lipase activity and found to possess moderate radical scavenging potential. The results of the above studies shows that the compounds synthesized on fibrate based pharmacophores might result in identification of new lead for dyslipidemia.
Subject(s)
Amides/chemical synthesis , Antioxidants/chemical synthesis , Fibric Acids/chemical synthesis , Hyperlipidemias/drug therapy , Hypolipidemic Agents/chemical synthesis , Lipoprotein Lipase/blood , Amides/pharmacology , Animals , Antioxidants/pharmacology , Enzyme Activation/drug effects , Fibric Acids/pharmacology , Free Radicals/antagonists & inhibitors , Hyperlipidemias/blood , Hyperlipidemias/chemically induced , Hyperlipidemias/enzymology , Hypolipidemic Agents/pharmacology , Lipid Peroxidation/drug effects , Male , Polyethylene Glycols , Rats , Structure-Activity RelationshipABSTRACT
First synthesis of novel coumarin-trioxane hybrids is reported. The synthesis was achieved via condensation of ß-hydroxyhydroperoxides with coumarinic-aldehydes in presence of p-toluenesulfonic acid in good yields and the novel hybrids were evaluated for their antimalarial activity both in vitro and in vivo.