The 4-aminoquinoline drugs, such as chloroquine (CQ), amodiaquine or piperaquine, are still commonly used for malaria treatment, either alone (CQ) or in combination with artemisinin derivatives. We previously described the excellent in vitro activity of a novel pyrrolizidinylmethyl derivative of 4-amino-7-chloroquinoline, named against drug-resistant parasites. Here, we report the optimized and safer synthesis of , now suitable for a scale-up, and its additional in vitro and in vivo characterization.
View Article and Find Full Text PDFTo improve the metabolic stability of a 4,4'-oxybisbenzoyl-based novel and potent (nanomolar-range IC ) antiplasmodial agent previously described by us, in silico-guided structure-activity relationship (SAR) campaigns have been conducted to substitute its peptide decorations with more metabolically stable residues. The effects of the various structural modifications were then correlated with the antiplasmodial activity in vitro in phenotypic assays. Among the several derivatives synthetized and compared with the 3D-pharmacophoric map of the original lead, a novel compound, characterized by a western tert-butyl glycine residue and an eastern 1S,2S-aminoacyclohexanol, showed low-nanomolar-range antiplasmodial activity, no signs of cross-resistance and, most importantly, 47-fold improved Phase I metabolic stability when incubated with human liver microsomes.
View Article and Find Full Text PDFPerfluorinated organic compounds (PFCs) are nontoxic, biocompatible, bioavailable, and bioorthogonal species which possess the unique ability to segregate away from both polar and nonpolar solvents producing a compact fluorophilic phase. Traditional techniques of fluorous chemical proteomics are generally applied to enrich biological samples in target protein(s) exploiting this property of PFCs to build fluorinated probes able to covalently bind to protein ensembles and being selectively extracted by fluorophilic solvents. Aiming at building a strategy able to avoid irreversible modification of the analyzed biosystem, a novel fully noncovalent probe is presented as an enabling tool for the recognition and isolation of biological protein(s).
View Article and Find Full Text PDFThe treatment of malaria, the most common parasitic disease worldwide and the third deadliest infection after HIV and tuberculosis, is currently compromised by the dramatic increase and diffusion of drug resistance among the various species of Plasmodium, especially P. falciparum (Pf). In this view, the development of new antiplasmodial agents that are able to act via innovative mechanisms of action, is crucial to ensure efficacious antimalarial treatments.
View Article and Find Full Text PDFArch Pharm (Weinheim)
December 2018
New therapeutics are urgently needed to fight tuberculosis and mycobacteria-related diseases that are a major health hazard especially in poor countries. Natural products have been the source of important antitubercular drugs in the past and still need to receive attention as a potent reservoir of chemical structures. Fifteen known and two new (+)-usnic acid (a benzofurandione formerly isolated from lichens) enamines and hydrazones are here described and tested against sensitive and multidrug-resistant strains of mycobacteria.
View Article and Find Full Text PDFNatural products are a prolific source for the identification of new biologically active compounds. In the present work, we studied the in vitro and in vivo antimalarial efficacy and ADME-Tox profile of a molecular hybrid (AM1) between 4-aminoquinoline and a quinolizidine moiety derived from lupinine (). The aim was to find a compound endowed with the target product profile-1 (TCP-1: molecules that clear asexual blood-stage parasitaemia), proposed by the Medicine for Malaria Venture to accomplish the goal of malaria elimination/eradication.
View Article and Find Full Text PDFGold nanocages (AuNCs) have been shown to be a useful tool for harnessing imaging and hyperthermia therapy of cancer, thanks to their unique optical properties, low toxicity, and facile surface functionalization. Herein, we use AuNCs for selective targeting of prostate cancer cells (PC3) via specific interaction between neuropeptide Y (NPY) receptor and three different NPY analogs conjugated to AuNCs. Localized surface plasmon resonance band of the nanoconjugates was set around 800 nm, which is appropriate for in vivo applications.
View Article and Find Full Text PDFTumor homing peptides (THPs) specific for a representative breast cancer cell line (MCF-7) were carefully selected basing on a phage-displayed peptide library freely available on the web, namely the "TumorHoPe: A Database of Tumor Homing Peptides". The selected THPs were synthesized and evaluated in terms of their affinity toward MCF-7 cells. Out of 5 tested THPs, 3 best-performing peptide sequences and 1 scrambled sequence were separately conjugated to spherical gold nanoparticles yielding stable nanoconjugates.
View Article and Find Full Text PDFMalaria is an infectious disease caused by Plasmodium parasites. It results in an annual death-toll of ~ 600,000. Resistance to all medications currently in use exists, and novel antimalarial drugs are urgently needed.
View Article and Find Full Text PDFBackground: Plasmodium falciparum serine repeat antigen 5 (PfSERA5) is an abundant blood stage protein that plays an essential role in merozoite egress and invasion. The native protein undergoes extensive proteolytic cleavage that appears to be tightly regulated. PfSERA5 N-terminal fragment is being developed as vaccine candidate antigen.
View Article and Find Full Text PDFOur previous studies showed that (-)-epigallocatechin-3-gallate (EGCG) inhibits signal transducer activator of transcription 1 (STAT1) activation. Since EGCG may be a promising lead compound for new anti-STAT1 drug design, 15 synthetic catechins, characterized by the (-)-gallocatechin-3-gallate stereochemistry, were studied in the human mammary MDA-MB-231 cell line to identify the minimal structural features that preserve the anti-STAT1 activity. We demonstrate that the presence of three hydroxyl groups of B ring and one hydroxyl group in D ring is essential to preserve their inhibitory action.
View Article and Find Full Text PDFAu naturel! (+)-Usnic acid (green) is a weak antimalarial agent, however, in conjugation with known antimalarial scaffolds and drugs, such as dihydroartemisinin (blue), potent activity against the blood-stage parasite can be seen both in vitro and in vivo. The compound shown exhibits an IC(50) value of 1.4 nM against Plasmodium falciparum in vitro and proved nearly as efficacious as artesunate in a mouse model of infection.
View Article and Find Full Text PDFRecently the N-(-)-lupinyl-derivative of 7-chloro-4-aminoquinoline ((-)-AM-1; 7-chloro-4-{N-[(1S,9aR)(octahydro-2H-quinolizin-1-yl)methyl]amino}quinoline) showed potent in vitro and in vivo activity against both Chloroquine susceptible and resistant strains of Plasmodium falciparum. However, (-)-AM-1 is synthesized starting from (-)-lupinine, an expensive alkaloid isolated from Lupinus luteus whose worldwide production is not sufficient, at present, for large market purposes. To overcome this issue, the corresponding racemic compound, derived from synthetic (±)-lupinine was considered a cheaper alternative for the development of a novel antimalarial agent.
View Article and Find Full Text PDFBioorg Med Chem Lett
September 2012
We report the discovery of new potent inhibitors of the growth of Plasmodium falciparum chloroquine (CQ)-resistant W2 strain. These compounds were designed using the double drug approach by introducing a residue able to enhance the accumulation of plasmepsins inhibitors into the food vacuole. Some of the molecules were more active than CQ against CQ-resistant strain and showed good selectivity against cathepsin D.
View Article and Find Full Text PDFSmall peptides that mimic the protein-protein interactions between falcipain-2 and egg white cystatin, an endogenous inhibitor of cysteine proteases, were designed and synthesized and their effects on falcipain-2 activity were analyzed. The mimics are characterized by the presence of different linkers: γ-aminobutyric acid, cis-4-aminocyclohexane carboxylic acid and a macrocycle formed by GABA and two cysteines joined by a disulfide linkage. Some of these compounds showed falcipain-2 inhibition in the micromolar range and produced morphological abnormalities in the Plasmodium food vacuole.
View Article and Find Full Text PDFAmphiphilic bile acids linked through an oligoethylene glycol to a biotin moiety were synthesized and shown to create micellar structures in aqueous environment, interact with avidin and be efficiently incorporated into hepatocyte cells, suggesting their potential as a drug delivery system against liver diseases.
View Article and Find Full Text PDFBackground: The sun-dried rind of the immature fruit of pomegranate (Punica granatum) is presently used as a herbal formulation (OMARIA, Orissa Malaria Research Indigenous Attempt) in Orissa, India, for the therapy and prophylaxis of malaria. The pathogenesis of cerebral malaria, a complication of the infection by Plasmodium falciparum, is an inflammatory cytokine-driven disease associated to an up-regulation and activity of metalloproteinase-9 and to the increase of TNF production. The in vitro anti-plasmodial activity of Punica granatum (Pg) was recently described.
View Article and Find Full Text PDFAim Of The Study: Sun-dried rind of the immature fruit of Punica granatum L. (Punicaceae) (Pg) is presently used as a herbal formulation (OMARIA) in Orissa, India, for the therapy and prophylaxis of malaria. The aims of this study were (i) to assess in vitro the antiplasmodial activity of the methanolic extract, of a tannin enriched fraction and of compounds/metabolites of the antimalarial plant, (ii) to estimate the curative efficacy of the Pg extracts and (iii) to explore the mechanism of action of the antiplasmodial compounds.
View Article and Find Full Text PDFBoth stereoisomer of hydroxyethylamine (HEA) and hydroxyethylsulfide (HES) transition-state isostere inhibitors of BACE-1 were synthesized. The syn-HEA epimer resulted always more active than the anti stereoisomer independently from the P(1) and the P(1)' substituents. On the contrary, the anti epimer of the HES isostere resulted more active than the syn stereoisomer.
View Article and Find Full Text PDFProtein Pept Lett
December 2008
Plasmepsin 4 (PM4) is a digestive vacuole enzyme found in all Plasmodium species examined to date. While P. falciparum has three additional aspartic proteinases in its digestive vacuole in addition to plasmepsin 4, other Plasmodium species have only PM4 in their digestive vacuole.
View Article and Find Full Text PDFBioorg Med Chem Lett
August 2008
The synthesis and antileishmanial activity of 18 edelfosine analogues are described. Compounds were obtained in parallel combining solid phase and solution phase synthesis. The most active analogue is characterized by the octadecyl group in position 2 of the glycerol chain.
View Article and Find Full Text PDFTo develop new classes of antimalarial agents, the possibility of replacing the phenolic ring of amodiaquine, tebuquine, and isoquine with other aromatic nuclei was investigated. Within a first set of pyrrole analogues, several compounds displayed high activity against both D10 (CQ-S) and W-2 (CQ-R) strains of Plasmodium falciparum. The isoquine structure was also modified by replacing the diethylamino group with more metabolically stable bicyclic moieties and by replacing the aromatic hydroxyl function with a chlorine atom.
View Article and Find Full Text PDFA series of [4-(2H-1,2,3-benzotriazol-2-yl)phenoxy]alkanoic acids has been synthesized and tested as agonists of Peroxisome Proliferator-Activated Receptor (PPAR) alpha, gamma, and delta. Three compounds displayed 56 to 96% of maximal activity of the reference drug Wy-14643 on PPARalpha, and two of these, i.e.
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