ABSTRACT
Cyclic oxyterpenes are natural products that are mostly used as fragrances, flavours and drugs by the cosmetic, food and pharmaceutical industries. However, only a few cyclic oxyterpenes are accessible via chemical syntheses, which are far from being ecofriendly. We report here the synthesis of six cyclic oxyterpenes derived from ß-pinene while respecting the principles of green and sustainable chemistry. Only natural or biosourced catalysts were used in mild conditions that were optimised for each synthesis. A new generation of ecocatalysts, derived from Mn-rich water lettuce, was prepared via green processes, characterised by MP-AES, XRPD and TEM analyses, and tested in catalysis. The epoxidation of ß-pinene led to the platform molecule, ß-pinene oxide, with a good yield, illustrating the efficacy of the new generation of ecocatalysts. The opening ß-pinene oxide was investigated in green conditions and led to new and regioselective syntheses of myrtenol, 7-hydroxy-α-terpineol and perillyl alcohol. Successive oxidations of perillyl alcohol could be performed using no hazardous oxidant and were controlled using the new generation of ecocatalysts generating perillaldehyde and cuminaldehyde.
Subject(s)
Green Chemistry Technology , Terpenes/chemical synthesis , Benzaldehydes/chemical synthesis , Benzaldehydes/chemistry , Bicyclic Monoterpenes/chemical synthesis , Bicyclic Monoterpenes/chemistry , Catalysis , Cymenes/chemical synthesis , Cymenes/chemistry , Elements , Monoterpenes/chemical synthesis , Monoterpenes/chemistry , Principal Component Analysis , Terpenes/chemistry , X-Ray DiffractionABSTRACT
We present the development of surfactant-free, silica-free and fully biobased oil-in-water antimicrobial Pickering emulsions, based on the self-assembly of ß-cyclodextrin and phytoantimicrobial oils (terpinen-4-ol or carvacrol). Undecylenic acid (UA), derived from castor oil, can be used as bio-based drug to treat fungal infection, but is less effective than petroleum-based drugs as azole derivatives. To maximize its antifungal potential, we have incorporated UA in fully biobased Pickering emulsions. These emulsions are effective against fungi, Gram-positive and Gram-negative bacteria. The carvacrol emulsion charged with UA is +390 % and +165 % more potent against methicillin-resistant S. aureus (MRSA), compared to UA and azole-based commercial formulations. Moreover, this emulsion is up to +480 % more efficient that UA ointment against C. albicans. Finally, remarkable eradication of E. coli and MRSA biofilms was obtained with this environmental-friendly emulsion.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Cymenes/pharmacology , Undecylenic Acids/pharmacology , beta-Cyclodextrins/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Candida albicans/drug effects , Castor Oil/chemistry , Cymenes/chemical synthesis , Cymenes/chemistry , Dose-Response Relationship, Drug , Emulsions/chemical synthesis , Emulsions/chemistry , Emulsions/pharmacology , Escherichia coli/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Undecylenic Acids/chemical synthesis , Undecylenic Acids/chemistry , beta-Cyclodextrins/chemical synthesis , beta-Cyclodextrins/chemistryABSTRACT
In an effort to develop a potent anti-malarial agent against Plasmodium falciparum, a structure-guided virtual screening using an in-house library comprising 652 compounds was performed. By docking studies, we identified two compounds (JMI-105 and JMI-346) which formed significant non-covalent interactions and fit well in the binding pocket of PfFP-2. We affirmed this observation by MD simulation studies. As evident by the biochemical analysis, such as enzyme inhibition assay, Surface Plasmon Resonance (SPR), live-cell imaging and hemozoin inhibition, JMI-105 and JMI-346 at 25 µM concentration showed an inhibitory effect on purified PfFP-2. JMI-105 and JMI-346 inhibited the growth of CQS (3D7; IC50 = 8.8 and 13 µM) and CQR (RKL-9; IC50 = 14.3 and 33 µM) strains of P. falciparum. Treatment with compounds resulted in defect in parasite growth and development. No significant hemolysis or cytotoxicity towards human cells was observed suggesting that these molecules are non-toxic. We pursued, structural optimization on JMI-105 and in the process, SAR oriented derivatives (5a-5l) were synthesized and evaluated for growth inhibition potential. JMI-105 significantly decreased parasitemia and prolonged host survival in a murine model with P. berghei ANKA infection. The compounds (JMI-105 and JMI-346) against PfFP-2 have the potential to be used as an anti-malarial agent.
Subject(s)
Antimalarials/pharmacology , Cymenes/pharmacology , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/pharmacology , Plasmodium falciparum/drug effects , Protozoan Proteins/antagonists & inhibitors , Antimalarials/chemical synthesis , Antimalarials/chemistry , Cymenes/chemical synthesis , Cymenes/chemistry , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Dose-Response Relationship, Drug , Models, Molecular , Molecular Structure , Parasitic Sensitivity Tests , Plasmodium falciparum/enzymology , Protozoan Proteins/metabolism , Structure-Activity RelationshipABSTRACT
In the present study, 23 novel carvacrol derivatives involving the amide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and tested in vitro as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. 2-(5-Isopropyl-2-methylphenoxy)-N-(quinolin-8-yl)acetamide (5v) revealed the highest inhibition properties against AChE and BuChE with the IC50 values of 1.93 and 0.05 µM, respectively. The blood-brain barrier (BBB) permeability of the potent inhibitor (5v) was also assessed by the widely used parallel artificial membrane permeability assay (PAMPA-BBB). The results showed that 5v is capable of crossing the BBB. Pharmacokinetic and toxicity profiles of the studied molecule predictions were investigated by MetaCore/MetaDrug comprehensive systems biology analysis suite. Bioactive conformations of the synthesized molecules, their predicted binding energies as well as structural and dynamical profiles of molecules at the binding pockets of AChE and BuChE targets were also investigated using different docking algorithms and molecular dynamics (MD) simulations.Communicated by Ramaswamy H. Sarma.
Subject(s)
Acetylcholinesterase/chemistry , Amides/chemical synthesis , Amides/pharmacology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacology , Cymenes/chemical synthesis , Cymenes/pharmacology , Molecular Docking Simulation , Acetylcholinesterase/metabolism , Amides/chemistry , Binding Sites , Blood-Brain Barrier/drug effects , Cholinesterase Inhibitors/chemistry , Cymenes/chemistry , Inhibitory Concentration 50 , Molecular Dynamics Simulation , Protein Domains , Toxicity TestsABSTRACT
Fine-tuning of the properties of a recently reported 1,3-indandione-based organoruthenium complex is attempted to optimize the stability under physiological conditions. Previous work has shown its capacity of inhibiting topoisomerase IIα; however, fast aquation leads to undesired reactions and ligand cleavage in the blood stream before the tumor tissue is reached. Exchange of the chlorido ligand for six different N-donor ligands resulted in new analogs that were stable at pH 7.4 and 8.5. Only a lowered pH level, as encountered in the extracellular space of the tumor tissue, was capable of aquating the complexes. The 50% inhibitory concentration (IC50) values in three human cancer cell lines differed only slightly, and their dependence on the utilized leaving group was smaller than what would be expected from their differences in cellular accumulation, but in accordance with the very minor variation revealed in measurements of the complexes' lipophilicity.
