Chagas disease and visceral leishmaniasis are two neglected tropical diseases responsible for numerous deaths around the world. For both, current treatments are largely inadequate, resulting in a ...continued need for new drug discovery. As both kinetoplastid parasites are incapable of de novo purine synthesis, they depend on purine salvage pathways that allow them to acquire and process purines from the host to meet their demands. Purine nucleoside analogues therefore constitute a logical source of potential antiparasitic agents. Earlier optimization efforts of the natural product tubercidin (7-deazaadenosine) involving modifications to the nucleobase 7-position and the ribofuranose 3′-position led to analogues with potent anti-Trypanosoma brucei and anti-Trypanosoma cruzi activities. In this work, we report the design and synthesis of pyrazolo3,4-dpyrimidine nucleosides with 3′- and 7-modifications and assess their potential as anti-Trypanosoma cruzi and antileishmanial agents. One compound was selected for in vivo evaluation in an acute Chagas disease mouse model.
Chagas disease (CD), a neglected tropical illness caused by the protozoan Trypanosoma cruzi, affects more than 6 million people mostly in poor areas of Latin America. CD has two phases: an acute, ...short phase mainly oligosymptomatic followed to the chronic phase, a long-lasting stage that may trigger cardiac and/or digestive disorders and death. Only two old drugs are available and both present low efficacy in the chronic stage, display side effects and are inactive against parasite strains naturally resistant to these nitroderivatives. These shortcomings justify the search for novel therapeutic options considering the target product profile for CD that will be presently reviewed besides briefly revisiting the data on phosphodiesterase inhibitors upon T. cruzi.
The tetracyclic phenolic compound brazilin, derived from the wood of Caesalpinia sappan, has been shown to bind to the chromatin protein BAF1 (barrier‐to‐autointegration factor 1), a protein ...essential to maintain integrity of the nuclear envelope in cells. BAF1 plays a role in cancer development. Using molecular docking, we have located the binding site for brazilin on the surface of the BAF1 monomer and compared its binding to that of four analogs. The oxidized product brazilein (ΔE = −57.7 kcal/mol) exhibits a higher affinity for BAF1 compared to the reduced form brazilin (ΔE = −38.2 kcal/mol). Incorporation of a 4‐hydroxyl substituent on the indenochromene unit affords hematoxylin and hematein. In silico analysis predicts that the oxidized form hematein (ΔE = −66.2 kcal/mol) displays a higher affinity for BAF1 than the reduced form hematoxylin (ΔE = −42.2 kcal/mol). In contrast, the atypical bis‐lactone product brazilide A cannot form good complexes with BAF1. The analysis points to the formation of more stable BAF1 complexes with the oxidized molecules compared to the reduced ones, but the position of the binding site on the protein cavity is different for brazilin/hematoxylin compared to brazilein/hematein. Our study may be useful to guide the design of BAF1 ligands.
BAF1 (barrier‐to‐autointegration factor 1) is an abundant, highly conserved double‐stranded DNA‐binding protein implicated in multiple cellular pathways, including cancer. The tetracyclic phenolic compound brazilin has been shown to bind to BAF1. Using molecular docking, we have located the binding site for brazilin on the surface of the BAF1 monomer and compared its binding to that of four analogs. Our study may be useful to guide the design of BAF1 ligands.
Chagas disease is becoming a worldwide problem; it is currently estimated that over six million people are infected. The two drugs in current use, benznidazole and nifurtimox, require long treatment ...regimens, show limited efficacy in the chronic phase of infection, and are known to cause adverse effects. Phenotypic screening of an in‐house library led to the identification of 2,2′‐methylenebis(5‐(4‐bromophenyl)‐4,4‐dimethyl‐2,4‐dihydro‐3H‐pyrazol‐3‐one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC50 value of 5.4 against Trypanosoma cruzi. Initial optimization was done by varying substituents of the phenyl ring, after which attempts were made to replace the phenyl ring. Finally, the linker between the dimer units was varied, ultimately leading to 2,2′‐methylenebis(5‐(3‐bromo‐4‐methoxyphenyl)‐4,4‐dimethyl‐2,4‐dihydro‐3H‐pyrazol‐3‐one (NPD‐0228) as the most potent analogue. NPD‐0228 has an in vitro pIC50 value of 6.4 against intracellular amastigotes of T. cruzi and no apparent toxicity against the human MRC‐5 cell line and murine cardiac cells.
Chagas disease is currently treated with only two drugs, benznidazole and nifurtimox, both of which show limited efficacy and certain adverse effects. In this study, phenotypic screening and subsequent optimization led to a bromophenyldihydropyrazole dimer (NPD‐0228), which is inactive against the bloodstream (trypomastigote) form of T. cruzi, but shows sub‐micromolar potency on the intracellular (amastigote) forms of the various parasite strains that are clinically relevant. As benznidazole is most active against the bloodstream form, NPD‐0228 might be well suited to combination treatments.
Extracts of the plant
Glycyrrhiza glabra
(licorice) are used in traditional medicine to treat malaria. The main active components are the saponin glycyrrhizin (GLR) and its active metabolite ...glycyrrhetinic acid (GA) which both display activities against
Plasmodium falciparum
. We have identified three main mechanisms at the origin of their anti-plasmodial activity: (i) drug-induced disorganisation of membrane lipid rafts, (ii) blockade of the alarmin protein HMGB1 and (iii) potential inhibition of the detoxifying enzyme glyoxalase 1 (GLO-1) considered as an important drug target for malaria. Our analysis shed light on the mechanism of action of GLR against
P. falciparum
.
More than 100 years after being first described, Chagas disease remains endemic in 21 Latin American countries and has spread to other continents. Indeed, this disease, which is caused by the ...protozoan parasite
, is no longer just a problem for the American continents but has become a global health threat. Current therapies, i.e., nifurtimox and benznidazole (Bz), are far from being adequate, due to their undesirable effects and their lack of efficacy in the chronic phases of the disease. In this work, we present an in-depth phenotypic evaluation in
of a new class of imidazole compounds, which were discovered in a previous phenotypic screen against different trypanosomatids and were designed as potential inhibitors of cAMP phosphodiesterases (PDEs). The confirmation of several activities similar or superior to that of Bz prompted a synthesis program of hit optimization and extended structure-activity relationship aimed at improving drug-like properties such as aqueous solubility, which resulted in additional hits with 50% inhibitory concentration (IC
) values similar to that of Bz. The cellular effects of one representative hit, compound 9, on bloodstream trypomastigotes were further investigated. Transmission electron microscopy revealed cellular changes, after just 2 h of incubation with the IC
concentration, that were consistent with induced autophagy and osmotic stress, mechanisms previously linked to cAMP signaling. Compound 9 induced highly significant increases in both cellular and medium cAMP levels, confirming that inhibition of
PDE(s) is part of its mechanism of action. The potent and selective activity of this imidazole-based PDE inhibitor class against
constitutes a successful repurposing of research into inhibitors of mammalian PDEs.
Leishmania is a trypanosomatid parasite that causes skin lesions in its cutaneous form. Current therapies rely on old and expensive drugs, against which the parasites have acquired considerable ...resistance. Trypanosomatids are unable to synthesize purines relying on salvaging from the host, and nucleoside analogues have emerged as attractive antiparasitic drug candidates. 4-Methyl-7-β-D-ribofuranosyl-7H-pyrrolo2,3-dpyrimidine (CL5564), an analogue of tubercidin in which the amine has been replaced by a methyl group, demonstrates activity against Trypanosoma cruzi and Leishmania infantum. Herein, we investigated its in vitro and in vivo activity against L. amazonensis. CL5564 was 6.5-fold (P = 0.0002) more potent than milteforan™ (ML) against intracellular forms in peritoneal mouse macrophages, and highly selective, while combination with ML gave an additive effect. These results stimulated us to study the activity of CL5564 in mouse model of cutaneous Leishmania infection. BALB/c female and male mice infected by L. amazonensis treated with CL5564 (10 mg kg−1, intralesional route for five days) presented a >93% reduction of paw lesion size likely ML given orally at 40 mg kg−1, while the combination (10 + 40 mg kg−1 of CL5564 and ML, respectively) caused >96% reduction. The qPCR confirmed the suppression of parasite load, but only the combination approach reached 66% of parasitological cure. These results support additional studies with nucleoside derivatives.
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