Antiplasmodial activity of p-substituted benzyl thiazinoquinone derivatives and their potential against parasitic infections

Malaria is a life-threatening disease and, what is more, the resistance to available antimalarial drugs is a recurring problem. The resistance of Plasmodium falciparum malaria parasites to previous generations of medicines has undermined malaria control efforts and reversed gains in child survival. This paper describes a continuation of our ongoing efforts to investigate the effects against Plasmodium falciparum strains and human microvascular endothelial cells (HMEC-1) of a series of methoxy p-benzyl-substituted thiazinoquinones designed starting from a pointed antimalarial lead candidate. The data obtained from the newly tested compounds expanded the structure-activity relationships (SARs) of the thiazinoquinone scaffold, indicating that antiplasmodial activity is not affected by the inductive effect but rather by the resonance effect of the introduced group at the para position of the benzyl substituent. Indeed, the current survey was based on the evaluation of antiparasitic usefulness as well as the selectivity on mammalian cells of the tested p-benzyl-substituted thiazinoquinones, upgrading the knowledge about the active thiazinoquinone scaffold

Investigating the antiparasitic potential of the marine sesquiterpene avarone, its reduced form avarol, and the novel semisynthetic thiazinoquinone analogue thiazoavarone

The chemical analysis of the sponge Dysidea avara afforded the known sesquiterpene quinone avarone, along with its reduced form avarol. To further explore the role of the thiazinoquinone scaffold as an antiplasmodial, antileishmanial and antischistosomal agent, we converted the quinone avarone into the thiazinoquinone derivative thiazoavarone. The semisynthetic compound, as well as the natural metabolites avarone and avarol, were pharmacologically investigated in order to assess their antiparasitic properties against sexual and asexual stages of Plasmodium falciparum, larval and adult developmental stages of Schistosomamansoni (eggs included), and also against promastigotes and amastigotes of Leishmania infantum and Leishmania tropica. Furthermore, in depth computational studies including density functional theory (DFT) calculations were performed. A toxic semiquinone radical species which can be produced starting both from quinone- and hydroquinone-based compounds could mediate the anti-parasitic effects of the tested compounds

Cooperative Binding of the Cationic Porphyrin Tris-T4 Enhances Catalytic Activity of 20S Proteasome Unveiling a Complex Distribution of Functional States

The present study provides new evidence that cationic porphyrins may be considered as tunable platforms to interfere with the structural "key code" present on the 20S proteasome α-rings and, by consequence, with its catalytic activity. Here, we describe the functional and conformational effects on the 20S proteasome induced by the cooperative binding of the tri-cationic 5-(phenyl)-10,15,20-(tri N-methyl-4-pyridyl) porphyrin (Tris-T4). Our integrated kinetic, NMR, and in silico analysis allowed us to disclose a complex effect on the 20S catalytic activity depending on substrate/porphyrin concentration. The analysis of the kinetic data shows that Tris-T4 shifts the relative populations of the multiple interconverting 20S proteasome conformations leading to an increase in substrate hydrolysis by an allosteric pathway. Based on our Tris-T4/h20S interaction model, Tris-T4 is able to affect gating dynamics and substrate hydrolysis by binding to an array of negatively charged and hydrophobic residues present on the protein surface involved in the 20S molecular activation by the regulatory proteins (RPs). Accordingly, despite the fact that Tris-T4 also binds to the α3ΔN mutant, allosteric modulation is not observed since the molecular mechanism connecting gate dynamics with substrate hydrolysis is impaired. We envisage that the dynamic view of the 20S conformational equilibria, activated through cooperative Tris-T4 binding, may work as a simplified model for a better understanding of the intricate network of 20S conformational/functional states that may be mobilized by exogenous ligands, paving the way for the development of a new generation of proteasome allosteric modulators

MS Dereplication for Rapid Discovery of Structurally New or Novel Natural Products

In order to accelerate the isolation and characterisation of structurally new or novel natural products, it is crucial to develop efficient strategies that prioritise samples with greatest promise early in the workflow so that resources can be utilised in a more efficient and cost-effective manner. Two complementary approaches have been developed: One is based on targeted identification of known compounds held in a database based on high resolution MS and predicted LC retention time data [1]. The second is an MS metrics-based approach where the software algorithm calculates metrics for sample novelty, complexity, and diversity after interrogating databases of known compounds, and contaminants. These metrics are then used to prioritise samples for isolation and structure elucidation work [2]. Both dereplication approaches have been validated using natural product extracts resulting in the isolation and characterization of new or novel natural products

Outstanding effects on antithrombin activity of modified TBA diastereomers containing an optically pure acyclic nucleotide analogue

Herein, we report optically pure modified acyclic nucleosides as ideal probes for aptamer modification. These new monomers offer unique advantages in exploring the role played in thrombin inhibition by a single residue modification at key positions of the TBA structure

Towards multi-stage drugs to fight poverty related and neglected parasitic diseases: synthetic and natural compounds directed against Leishmania, Plasmodium and Schistosoma life stages and assessment of their mechanisms of action

Malaria, leishmaniasis and schistosomiasis rank among the most devastating tropical diseases in the world. A core group of Italian scientists, with a long standing experience in Neglected Tropical Diseases and Poverty Related Diseases (NTDs and PRDs), decided to create the LeishPlaSch Consortium to bring their knowledge and their efforts together with the aim of achieving substantial advancements in the discovery of novel therapeutic and/or preventive drugs against Plasmodium, Leishmania and Schistosoma, the pathogens causing malaria (a PRD), leishmaniosis and schistosomiasis (PRDs and NTDs, respectively). There are three main arguments that constitute the rationale for the choice of the project’s target parasitic diseases: -All 3 parasites develops in the human host plus an invertebrate host/vector and all - at some stage of their life cycle - reproduce and/or mature in the blood of the human host; -There is evidence for multi-parasite activity of various drugs and molecules belonging to different chemical classes, e.g. artemisins exhibit activity on Plasmodium, Leishmania and Schistosoma; -The epidemiology and control of all 3 diseases is influenced by socioeconomic conditions, malnutrition, population mobility, environmental and climate changes. The goal of the proposal is to develop new, deployable products with targeted profiles against malaria, leishmaniasis and schistosomiasis, in particular by identifying new chemical entities appropriate for the pharmacological management of malaria, leishmaniasis and schistosomiasis. The goals of the LeishPlaSch consortium are: 1-Identification of disease specific and/or multi-antiparasitic new lead compounds, including repurposing approaches; 2-Identification of compounds with multistage effects for the development of combination treatments including transmission-blocking activity; 3-Validation of novel targets for drug discovery, including a structural biology approach; 4-Advancement of understanding parasite biology and drug-related host parasite relationships, including the definition of modes of action, and identification of new target pathways. LeishPlaSch Consortium will exploit the high scientific skills of Italian parasitologists, structural and molecular biologists, medicinal and natural organic chemists, biochemists, immunologists, and bioinformaticians. Most of the LeishPlaSch partners are active members of the Italian Malaria Network and already synergized their activities in EC funded projects such as FP6-AntiMal and BioMalPar, and FP7-EVIMalaR and InterMalTraining. The organization of the LeishPlaSch consortium is organized on 3 WPs, based on 3 main platforms: a Chemistry Platform, an Enzymatic and a Phenotypic in vitro platform and in vivo screening Platform. All three WPs will combine their interdisciplinary efforts to identify, select and investigate the mode of action of novel antiparasitic compounds