Discovery of 1,3,4,5-tetrasubstituted pyrazoles as anti-trypanosomatid agents: Identification of alterations in flagellar structure of L. amazonensis

Silva, Michael J. V. da; Jacomini, Andrey P.; Gonçalves, Davana S.; Pianoski, Karlos Eduardo; Poletto, Julia; Lazarin-Bidóia, Danielle; Volpato, Hélito; Nakamura, Celso V.; Rosa, Fernanda A.

doi:10.1016/j.bioorg.2021.105082

Cited by 6 publications

(3 citation statements)

References 36 publications

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“…Similarly, prenylated chalcones [144] and prenyloxy chalcones [145] have demonstrated both anti-leishmanial and anti-trypanosomal activity. Additional compound classes that have shown potent anti-kinetoplastid activity include binuclear cyclopalladated compounds [146], 1,3,4,5-tetrasubstituted pyrazoles [147], N,N -dihetaryl substituted diamines [148], N-benzene and N-naphthalenesulfonamide derivatives [149], thiazolyl-isatin derivatives [150], and ruthenium-purine complexes [151]. Natural products have also been an area of interest, with several researchers identifying compounds like sesquiterpene lactones [152,153] and terpenoids [154] with anti-trypanosomatid properties.…”

Section: Drug Discovery Targeting Multiple Eukaryotic and Prokaryotic...mentioning

confidence: 99%

Drug Discovery for Cutaneous Leishmaniasis: A Review of Developments in the Past 15 Years

Corman,

McNamara,

Bakowski

2023

Microorganisms

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Leishmaniasis is a group of vector-borne, parasitic diseases caused by over 20 species of the protozoan Leishmania spp. The three major disease classifications, cutaneous, visceral, and mucocutaneous, have a range of clinical manifestations from self-healing skin lesions to hepatosplenomegaly and mucosal membrane damage to fatality. As a neglected tropical disease, leishmaniasis represents a major international health challenge, with nearly 350 million people living at risk of infection a year. The current chemotherapeutics used to treat leishmaniasis have harsh side effects, prolonged and costly treatment regimens, as well as emerging drug resistance, and are predominantly used for the treatment of visceral leishmaniasis. There is an undeniable need for the identification and development of novel chemotherapeutics targeting cutaneous leishmaniasis (CL), largely ignored by concerted drug development efforts. CL is mostly non-lethal and the most common presentation of this disease, with nearly 1 million new cases reported annually. Recognizing this unaddressed need, substantial yet fragmented progress in early drug discovery efforts for CL has occurred in the past 15 years and was outlined in this review. However, further work needs to be carried out to advance early discovery candidates towards the clinic. Importantly, there is a paucity of investment in the translation and development of therapies for CL, limiting the emergence of viable solutions to deal with this serious and complex international health problem.

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Section: Drug Discovery Targeting Multiple Eukaryotic and Prokaryotic...mentioning

confidence: 99%

Drug Discovery for Cutaneous Leishmaniasis: A Review of Developments in the Past 15 Years

Corman,

McNamara,

Bakowski

2023

Microorganisms

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“…Pyrazoles and their derivatives stand out in the field of medicinal chemistry [ 20 ], as they represent a relevant class of compounds with broad biological activities already reported as antioxidants [ 21 ], antiviral [ 22 ], antimicrobial [ 23 ], anticancer [ 24 ], and anti-inflammatory [ 25 ], among others. Pyrazole derivatives have been highlighted for their effects on trypanosomatids [ 26 ]. Pyrazole-trifluoromethylated hybrids have potent activity against Leishmania amazonensis and T. cruzi , with the pyrazole 2-amino-1,3,4-thiadiazole hybrids considered as a relevant scaffold for optimization [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against Trypanosoma cruzi: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease

et al. 2022

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Chagas disease, a century-old disease that mainly affects the impoverished population in Latin America, causes high morbidity and mortality in endemic countries. The available drugs, benznidazole (Bz) and nifurtimox, have limited effectiveness and intense side effects. Drug repurposing, and the development of new chemical entities with potent activity against Trypanosoma cruzi, are a potential source of therapeutic options. The present study describes the biological activity of two new series of pyrazole-thiazoline derivatives, based on optimization of a hit system 5-aminopyrazole-imidazoline previously identified, using structure–activity relationship exploration, and computational and phenotype-based strategies. Promising candidates, 2c, 2e, and 2i derivatives, showed good oral bioavailability and ADMET properties, and low cytotoxicity (CC50 > 100 µM) besides potent activity against trypomastigotes (0.4–2.1 µM) compared to Bz (19.6 ± 2.3 µM). Among them, 2c also stands out, with greater potency against intracellular amastigotes (pIC50 = 5.85). The selected pyrazole-thiazoline derivatives showed good permeability and effectiveness in the 3D spheroids system, but did not sustain parasite clearance in a washout assay. The compounds’ mechanism of action is still unknown, since the treatment neither increased reactive oxygen species, nor reduced cysteine protease activity. This new scaffold will be targeted to optimize in order to enhance its biological activity to identify new drug candidates for Chagas disease therapy.

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“…These structures are recognized for their high anticancer, antifungal, antiparasitic, antitubercular, cytotoxic, and herbicidal characteristics [1][2][3][4]. The substitution of the R and R groups with functionalized aromatic or heterocyclic moieties has been shown to be a promising pharmacological strategy to enhance the biological activity of azomethine ligands as anti-inflammatory [5], antitumor [6,7], antimicrobial [8], antidiabetic [9], antileishmaniacic [10], and antitubercular [11] agents, among others [12,13]. R substituted azomethine derivatives with functionalized pyrazole rings have revealed both potent and varied biological activities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Structural Characterization, and In Vitro and In Silico Antifungal Evaluation of Azo-Azomethine Pyrazoles (PhN2(PhOH)CHN(C3N2(CH3)3)PhR, R = H or NO2)

et al. 2021

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The azo-azomethine imines, R1-N=N-R2-CH=N-R3, are a class of active pharmacological ligands that have been prominent antifungal, antibacterial, and antitumor agents. In this study, four new azo-azomethines, R1 = Ph, R2 = phenol, and R3 = pyrazol-Ph-R’ (R = H or NO2), have been synthesized, structurally characterized using X-ray, IR, NMR and UV–Vis techniques, and their antifungal activity evaluated against certified strains of Candida albicans and Cryptococcus neoformans. The antifungal tests revealed a high to moderate inhibitory activity towards both strains, which is regulated as a function of both the presence and the location of the nitro group in the aromatic ring of the series. These biological assays were further complemented with molecular docking studies against three different molecular targets from each fungus strain. Molecular dynamics simulations and binding free energy calculations were performed on the two best molecular docking results for each fungus strain. Better affinity for active sites for nitro compounds at the “meta” and “para” positions was found, making them promising building blocks for the development of new Schiff bases with high antifungal activity.

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Discovery of 1,3,4,5-tetrasubstituted pyrazoles as anti-trypanosomatid agents: Identification of alterations in flagellar structure of L. amazonensis

Cited by 6 publications

References 36 publications

Drug Discovery for Cutaneous Leishmaniasis: A Review of Developments in the Past 15 Years

Drug Discovery for Cutaneous Leishmaniasis: A Review of Developments in the Past 15 Years

Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against Trypanosoma cruzi: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease

Synthesis, Structural Characterization, and In Vitro and In Silico Antifungal Evaluation of Azo-Azomethine Pyrazoles (PhN2(PhOH)CHN(C3N2(CH3)3)PhR, R = H or NO2)

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