Abstract:Five bis-arylimidamides were assayed as anti- agents by ,, and approaches. None were considered to be pan-assay interference compounds. They had a favorable pharmacokinetic landscape and were active against trypomastigotes and intracellular forms, and in combination with benznidazole, they gave no interaction. The most selective agent (28SMB032) tested led to a 40% reduction in parasitemia (0.1 mg/kg of body weight/5 days intraperitoneally) but without mortality protection. target fishing suggested DNA as the … Show more
“…These events might be linked to defects in osmoregulation, which is thought to be one of the functions of cAMP signaling in T. cruzi (15). In addition, large numbers of myelin figures were observed, as well as membranous enclosures surrounding cytoplasmic organelles, which are the morphological characteristics of autophagy, as reported for other trypanocidal compounds (16). Autophagy is a process involved in life cycle progression and differentiation, and cAMP signaling in Leishmania has been directly linked to autophagy and differentiation (17).…”
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 Trypanosoma cruzi, 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 T. cruzi 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 50 ) 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 50 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 T. cruzi PDE(s) is part of its mechanism of action. The potent and selective activity of this imidazole-based PDE inhibitor class against T. cruzi constitutes a successful repurposing of research into inhibitors of mammalian PDEs.
“…These events might be linked to defects in osmoregulation, which is thought to be one of the functions of cAMP signaling in T. cruzi (15). In addition, large numbers of myelin figures were observed, as well as membranous enclosures surrounding cytoplasmic organelles, which are the morphological characteristics of autophagy, as reported for other trypanocidal compounds (16). Autophagy is a process involved in life cycle progression and differentiation, and cAMP signaling in Leishmania has been directly linked to autophagy and differentiation (17).…”
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 Trypanosoma cruzi, 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 T. cruzi 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 50 ) 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 50 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 T. cruzi PDE(s) is part of its mechanism of action. The potent and selective activity of this imidazole-based PDE inhibitor class against T. cruzi constitutes a successful repurposing of research into inhibitors of mammalian PDEs.
“…The "in-silico" analysis which stands for computer-based biological experiments, is a state-of-the-art and accurate method to discover exclusive bioactive compounds, which may represent novel metabolic pathways and/or a powerful affinity to a certain target (42). In this sense, several studies have identified unprecedented molecules for various drug targets in Leishmania, such as pteridine reductase1, tryparedoxin peroxidase and sterol biosynthesis (43)(44)(45)(46)(47)(48), as well as in other single-celled eukaryotes enclosing Toxoplasma gondii, Cryptosporidium hominis, Plasmodium and Trypanosoma cruzi (49)(50)(51). Current in-silico investigation was aimed to screen and predict the anti-leishmanial potency of 3358 FDA-approved compounds against both drug targets in L. infantum in comparison to amphotericin B and glucantime for the discovery of new biochemical molecules.…”
Amaç: Mevcut in-silico araştırması, Leishmania infantum lipofosfoglikan (LPG) ve γ-glutamilsistein sentetazına (γ-GCS) karşı umut verici ilaçlar bulmak amacıyla 20000 Gıda ve İlaç İdaresi onaylı ilaç bileşiklerinin taranması için tasarlandı ve uygulandı. Yöntemler: Her iki hedefin protein sekansı alındıktan sonra, 3D yapıları tahmin edildi ve doğrulandı. Moleküler yerleştirme iki varsayılan hedef (LPG ve γ-GCS) arasında yapıldı ve ligand-reseptör etkileşimlerini tahmin etmek için AutoDock 4.2 programı kullanılarak onaylanmış bileşikler seçildi. Bulgular: Yirmi bin ilaç bileşiği üzerinde deney yapıldıktan sonra, γ-GCS reseptörü için iki ve LPG reseptörü için beş olmak üzere toplam yedi ligand, bağlanma afiniteleri ve enerjilerine göre yeni, güçlü anti-leishmanial ilaçlar olarak belirlenmiştir. Bunlardan 5 ligand 8,5 kcal/mol'e kadar daha negatif Δ Gbinding ile LPG reseptörüne iyi bağlanma kapasitesi gösteren sitotoksik ve anti-kanser özelliklere sahipti. Bunlardan 2 ligand, 7,8 kcal/mol'e kadar daha negatif Δ Gbinding ile glutamil reseptörüne iyi bir bağlanma kapasitesi gösterdi. Sonuç: En yeni yazılım tabanlı yöntemler, yeni ilaç keşfi için organizmalarda biyolojik hedeflere özgü yeni peptid şablonlarını taramak ve tahmin etmek için güçlü araçlardır. Bununla birlikte, in vitro ve in vivo tekniklerin kullanımı, öngörülen ligandların öz Objective: Current in-silico research was designed and administered for the screening of 20000 Food and Drug Administrationapproved drug compounds with the goal of finding promising drugs against lipophosphoglycan (LPG) and γ-glutamylcysteine synthetase (γ-GCS) of Leishmania infantum. Methods: After the protein sequence of both targets was taken, the 3D structures of protein of interest were predicted and validated. Molecular docking was done among the two putative targets (LPG and γ-GCS) and approved compounds were selected using AutoDock 4.2 program to predict ligand-receptor interactions. Results: After docking experiment was done on 20000 drug compounds, a total number of seven ligands, two for γ-GCS receptor and five for LPG receptor, were assigned as novel, potent anti-leishmanial drugs based on their binding affinity and energy. Of those, five ligands possessed cytotoxic and anti-cancer characteristics and showed good binding capacity to LPG receptor with Δ Gbinding up to 8.5 kcal/mol more negative; while two compounds showed good binding capacity to glutamyl receptor with Δ Gbinding up to 7.8 kcal/mol more negative. Conclusion: The latest software-based methods are powerful tools for scanning and predicting new peptide templates specific to biological targets in organisms for new drug discovery. However, the use of in vitro and in vivo techniques is a requirement for better evaluation of the potential of projected ligands with the help of in-silico approaches, identifying molecular mechanism of action of the more active compounds is possible. This can help in defining the most likely molecular target, so that the subsequent optimization using in vitro and in vivo techniques ...
“…All 32 identified hit compounds (Figs 1 and 2) that were purchased from Asinex commercial vendor and the reference drug, pentamidine (Pt), were dissolved in 99.99% dimethyl sulphoxide (DMSO) (stock solutions at 20 m m ) and fresh dilutions prepared extemporaneously, with the final concentration never exceeding 0.6% DMSO for in vitro experiments, which does not induce host cell toxicity (Santos et al ., 2018). Fig.…”
Section: Methodsmentioning
confidence: 99%
“…In these assays, PMM (3 × 10 5 ) were infected with amastigotes (9 × 10 5 amastigotes) using multiplicity of infection (MOI) 3:1 (Van Bocxlaer et al ., 2019). After 48 h of compound incubation (0–20 μ m ), infected PMM were rinsed with saline buffered with phosphate (PBS), fixed with Bouin's solution and stained with Giemsa for light microscopy analysis (Santos et al ., 2018). Then, the percentage of infected host cells and the number of parasites per infected cells were scored for determination of the corresponding infection index (II) that represents the multiplication factor of both parameters.…”
Cutaneous leishmaniasis (CL) is one of the most disregarded tropical neglected disease with the occurrence of self-limiting ulcers and triggering mucosal damage and stigmatizing scars, leading to huge public health problems and social negative impacts. Pentavalent antimonials are the first-line drug for CL treatment for over 70 years and present several drawbacks in terms of safety and efficacy. Thus, there is an urgent need to search for non-invasive, non-toxic and potent drug candidates for CL. In this sense, we have implemented a shape-based virtual screening approach and identified a set of 32 hit compounds. In vitro phenotypic screenings were conducted using these hit compounds to check their potential leishmanicidal effect towards Leishmania amazonensis (L. amazonensis). Two (Cp1 and Cp2) out of the 32 compounds revealed promising antiparasitic activities, exhibiting considerable potency against intracellular amastigotes present in peritoneal macrophages (IC50 values of 9.35 and 7.25 μm, respectively). Also, a sterile cidality profile was reached at 20 μm after 48 h of incubation, besides a reasonable selectivity (≈8), quite similarly to pentamidine, a diamidine still in use clinically for leishmaniasis. Cp1 with an oxazolo[4,5-b]pyridine scaffold and Cp2 with benzimidazole scaffold could be developed by lead optimization studies to enhance their leishmanicidal potency.
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