Exploring novel pyrazole-nitroimidazole hybrids: Synthesis and antiprotozoal activity against the human pathogen trichomonas vaginalis.

Trichomoniasis, a prevalent sexually transmitted infection (STI) caused by the protozoan Trichomonas vaginalis, has gained increased significance globally. Its relevance has grown in recent years due to its association with a heightened risk of acquiring and transmitting the human immunodeficiency virus (HIV) and other STIs. In addition, many publications have revealed a potential link between trichomoniasis and certain cancers. Metronidazole (MTZ), a nitroimidazole compound developed over 50 years ago, remains the first-choice drug for treatment. However, reports of genotoxicity and side effects underscore the necessity for new compounds to address this pressing global health concern. In this study, we synthesized ten pyrazole-nitroimidazoles 1(a-j) and 4-nitro-1-(hydroxyethyl)-1H-imidazole 2, an analog of metronidazole (MTZ), and assessed their trichomonacidal and cytotoxic effects. All compounds 1(a-j) and 2 exhibited IC50 values ≤ 20 µM and ≤ 41 µM, after 24 h and 48 h, respectively. Compounds 1d (IC50 5.3 µM), 1e (IC50 4.8 µM), and 1i (IC50 5.2 µM) exhibited potencies equivalent to MTZ (IC50 4.9 µM), the reference drug, after 24 h. Notably, compound 1i showed high anti-trichomonas activity after 24 h (IC50 5.2 µM) and 48 h (IC50 2.1 µM). Additionally, all compounds demonstrated either non-cytotoxic to HeLa cells (CC50 > 100 µM) or low cytotoxicity (CC50 between 69 and 100 µM). These findings suggest that pyrazole-nitroimidazole derivatives represent a promising heterocyclic system, serving as a potential lead for further optimization in trichomoniasis chemotherapy.

A Review of the Synthesis of Oxazoline Derivatives.

Oxazolines are important heterocyclic systems due to their biological activities, such as antibacterial, antimalarial, anticancer, antiviral, anti-inflammatory, antifungal, antipyretic, and antileishmanial. They have been widely applied as chiral auxiliaries, polymers, catalysts, protecting groups, building blocks, and ligands in asymmetric synthesis. Due to their importance, many synthetic routes to prepare oxazoline moieties have been investigated and developed by researchers around the world. In this review, we summarized several synthetic methodologies published in the literature. The main substrates are nitriles, carboxylic acids, and acid derivatives, which react with a variety of reactants under conventional heating, microwave irradiation or ultrasound irradiation conditions. Syntheses via intramolecular cyclisation from amides have also been reported. Many publications have highlighted procedures based on solvent-free conditions using eco-friendly, reusable, and easy-availability catalysts.

Synthesis by Microwave Irradiation, Molecular Structural Analysis and Trypanocidal Activity of Novel Pyrazole-tetrahydropyrimidine Derivatives.

BACKGROUND: A series of new eight 2-(1-aryl-3-methyl-1H-pyrazol-4-yl)-1,4,5,6-tetrahydropyrimidines 1(a-h) were synthesized by microwave irradiation technique. In vitro phenotypic screening was performed to evaluate the effect of these compounds on intracellular amastigotes forms of Trypanosoma cruzi, the etiological agent of Chagas disease. METHODS: Compounds 1(a-h) were synthesized from pyrazole-carbonitriles 2(a-h) employing microwave irradiation (50W) for 10-20 minutes. Physicochemical properties were calculated using OSIRIS DataWarrior. The toxic effect on mammalian cells (Vero Cells) and the trypanocidal activity against Trypanosoma cruzi (Dm28c-Luc) were also evaluated. RESULTS: Compounds 1(a-h) were obtained in 24-94% yields. They were completely characterized by Fourier Transform Infrared (FT-IR), Nuclear Magnetic Resonance (NMR) and High-Resolution Mass Spectrometry (HRMS) analyses. The derivatives showed low trypanocidal activity, with IC50 ranging from 47.16 to > 100 µM, with lower activity than benznidazole (1.93 µM) used as reference drug. CONCLUSION: The attractive features of this synthetic methodology are mild conditions, short reaction time, and low power. All derivatives showed low toxicity in mammalian cells, good oral bioavailability, and did not violate Lipinski´s rule of 5.

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

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.

Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against Trypanosoma cruzi.

Chagas disease, a chronic and silent disease caused by Trypanosoma cruzi, is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and nifurtimox, two nitroheterocyclic drugs that show limited efficacy and severe side effects. The failure of potential drug candidates in Chagas disease clinical trials highlighted the urgent need to identify new effective chemical entities and more predictive tools to improve translational success in the drug development pipeline. In this study, we designed a small library of pyrazole derivatives (44 analogs) based on a hit compound, previously identified as a T. cruzi cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds 3g, 3j, and 3m as promising candidates, with IC50 values of 6.09 ± 0.52, 2.75 ± 0.62, and 3.58 ± 0.25 µM, respectively, against intracellular amastigotes. All pyrazole derivatives have good oral bioavailability prediction. The structure-activity relationship (SAR) analysis revealed increased potency of 1-aryl-1H-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the para-position. The 3m compound stands out for its trypanocidal efficacy in 3D microtissue, which mimics tissue microarchitecture and physiology, and abolishment of parasite recrudescence in vitro. Our findings encourage the progression of the promising candidate for preclinical in vivo studies.

Recently reported biological activities of pyrazole compounds.

The pyrazole nucleus is an aromatic azole heterocycle with two adjacent nitrogen atoms. Pyrazole derivatives have exhibited a broad spectrum of biological activities, and approved pyrazole-containing drugs include celecoxib, antipyrine, phenylbutazone, rimonabant, and dipyrone. Many research groups have synthesized and evaluated pyrazoles against several biological agents. This review examines recent publications relating the structures of pyrazoles with their corresponding biological activities.

The new pyrazolyltetrazole derivative MSN20 is effective via oral delivery against cutaneous leishmaniasis.

An orally delivered, safe and effective treatment for leishmaniasis is an unmet medical need. Azoles and the pyrazolylpyrimidine allopurinol present leishmanicidal activity, but their clinical efficacies are variable. Here, we describe the activity of the new pyrazolyltetrazole hybrid, 5-[5-amino-1-(4'-methoxyphenyl)1H-pyrazole-4-yl]1H-tetrazole (MSN20). MSN20 showed a 50% inhibitory concentration (IC50) of 22.3 µM against amastigotes of Leishmania amazonensis and reduced significantly the parasite load in infected mice, suggesting its utility as a lead compound for the development of an oral treatment for leishmaniasis.