ABSTRACT
Artemisinin-based combination therapies (ACTs) have been able to reduce the clinical and pathological malaria cases in endemic areas around the globe. However, recent reports have shown a progressive decline in malaria parasite clearance in South-east Asia after ACT treatment, thus envisaging a need for new artemisinin (ART) derivatives and combinations. To address the emergence of drug resistance to current antimalarials, here we report the synthesis of artemisinin-peptidyl vinyl phosphonate hybrid molecules that show superior efficacy than artemisinin alone against chloroquine-resistant as well as multidrug-resistant Plasmodium falciparum strains with EC50 in pico-molar ranges. Further, the compounds effectively inhibited the survival of ring-stage parasite for laboratory-adapted artemisinin-resistant parasite lines as compared to artemisinin. These hybrid molecules showed complete parasite clearance in vivo using P. berghei mouse malaria model in comparison to artemisinin alone. Studies on the mode of action of hybrid molecules suggested that these artemisinin-peptidyl vinyl phosphonate hybrid molecules possessed dual activities: inhibited falcipain-2 (FP-2) activity, a P. falciparum cysteine protease involved in hemoglobin degradation, and also blocked the hemozoin formation in the food-vacuole, a step earlier shown to be blocked by artemisinin. Since these hybrid molecules blocked multiple steps of a pathway and showed synergistic efficacies, we believe that these lead compounds can be developed as effective antimalarials to prevent the spread of resistance to current antimalarials.
Subject(s)
Antimalarials/pharmacology , Drug Resistance, Multiple/drug effects , Malaria/drug therapy , Plasmodium falciparum/drug effects , Antimalarials/chemical synthesis , Antimalarials/chemistry , Artemisinins/chemical synthesis , Artemisinins/chemistry , Artemisinins/pharmacology , Cysteine Endopeptidases/metabolism , Dose-Response Relationship, Drug , Heme/antagonists & inhibitors , Heme/metabolism , Malaria/metabolism , Molecular Structure , Organophosphonates/chemical synthesis , Organophosphonates/chemistry , Organophosphonates/pharmacology , Parasitic Sensitivity Tests , Peptides/chemical synthesis , Peptides/chemistry , Peptides/pharmacology , Polymerization/drug effects , Structure-Activity Relationship , Vinyl Compounds/chemical synthesis , Vinyl Compounds/chemistry , Vinyl Compounds/pharmacologyABSTRACT
A small library of structurally diverse α-aminophosphonates has been synthesized by reacting alkyl/aryl aldehydes, alkyl/aryl amines and alkyl/aryl phosphites in one-pot catalyzed by Amberlite-IR 120 resin (acidic). All the synthesized α-aminophosphonates were assayed for their in vitro cytotoxic activities against a panel of five human cancer cell lines including A-549, NCI-H23 (Lung), Colo 320DM (Colon), MG-63 (Bone marrow) and Jurkat (Blood T lymphocytes). Compound 4n having (R)-1-phenylethanamine was found to be the most active amongst all the synthesized α-aminophosphonates against all the five cancer cell lines, most prominent being against Jurkat cell line with an IC50 value of 4 µM. Surprisingly, compound 4o having (S)-1-phenylethanamine was found to be devoid of any cytotoxicity. Our finding suggests that these chemical entities could further serve as interesting template for the design of potential anticancer agents.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Organophosphonates/chemical synthesis , Organophosphonates/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Cell Line, Tumor , Chemistry Techniques, Synthetic , Humans , Organophosphonates/chemistry , Organophosphonates/metabolism , PermeabilityABSTRACT
HIV protease is a promising drug target for AIDS therapy, and several potent HIV-1 protease inhibitors have been reported to date. Although existing inhibitors exhibit high selectivity, they have also been associated with severe side effects and the possible emergence of therapeutic resistance. As HIV protease cleaves the peptide bond via a tetrahedral intermediate, various transition-state models such as hydroxyethylamine (HEA) have been designed. We therefore pursued an efficient synthesis of an HEA isostere; this was performed with a novel one-pot reduction-transimination-reduction reaction sequence as a key step. α-Aminophosphonate and phosphoramidate derivatives of the HEA isostere were designed and synthesized, and all of the synthesized derivatives were assayed for their anti-HIV activities against wild-type and mutant HIV strains. Phosphoramidate derivative 15 a was found to be the most active of all synthesized compounds against the III(B) and RES056 strains. As phosphonates are known to exhibit physiological stability, good cell permeability, and other promising pharmacokinetic characteristics, our newly synthesized compounds have the potential as alternatives to existing therapeutics and diagnostics.
Subject(s)
Amides/pharmacology , Ethylamines/pharmacology , HIV Protease Inhibitors/pharmacology , HIV/drug effects , Phosphoric Acids/pharmacology , Amides/chemistry , Cell Line , Ethylamines/chemistry , HIV/enzymology , HIV Infections/drug therapy , HIV Protease Inhibitors/chemistry , Humans , Models, Molecular , Phosphoric Acids/chemistry , Structure-Activity RelationshipABSTRACT
We report herein, design and synthesis of vinylaminophosphonates, a novel class of compounds as possible cysteine protease inhibitors. The synthesis of vinylaminophosphonates has been accomplished employing Tsuji-Trost reaction as a key step. The synthesized compounds were assayed against papain, a model cysteine protease and some of our synthesized compounds showed IC(50) values in the range of 30-54 µM thereby suggesting that these chemical entities thus could constitute an interesting template for the design of potential novel protease inhibitors.
Subject(s)
Cysteine Proteinase Inhibitors/chemistry , Organophosphonates/chemistry , Organophosphonates/pharmacology , Peptides/chemistry , Peptides/pharmacology , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/pharmacology , Humans , Models, Molecular , Molecular Structure , Organophosphonates/chemical synthesis , Peptides/chemical synthesis , Spectroscopy, Fourier Transform Infrared , Structure-Activity Relationship , Vinyl Compounds/chemical synthesis , Vinyl Compounds/chemistry , Vinyl Compounds/pharmacologyABSTRACT
A novel one-pot route for the synthesis of benzodiazepinyl phosphonates (BDPs) has been achieved. FeCl(3) efficiently catalyzed four-component condensation of diamines, acetone and phosphites in the presence of molecular sieves to furnish BDPs as novel chemical entities with good yield. The synthesized BDPs have shown significant protease inhibition activity against clostripain, a disease model for gas gangrene, suggesting that these novel chemical entities could be further explored as cysteine protease inhibitors.
Subject(s)
Chlorides/chemistry , Cysteine Endopeptidases/drug effects , Cysteine Proteinase Inhibitors/chemical synthesis , Ferric Compounds/chemistry , Organophosphonates/chemical synthesis , Catalysis , Cysteine Endopeptidases/chemistry , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Molecular Structure , Organophosphonates/chemistry , Organophosphonates/pharmacologyABSTRACT
A simple and expedient method for the synthesis of a series of 14-aryl-14H-dibenzo[a.j]xanthenes is described through a one-pot condensation of beta-naphthol with aryl aldehydes catalysed by TaCl5 under solvent-free conventional heating. The major advantages of the present method are: high yields, less reaction time, solvent-free condition and easy purification of the products. The synthesized 14-aryl-14H-dibenzo[a.j]xanthenes were evaluated against a panel of six human cancer lines of different tissues. Synthesized compound 3o showed IC50 of 37.9 and 41.3 microM against Colo-205 and 502713, respectively, whereas 3g showed IC50 of 41.9 microM against Colo-205.
