Synthesis, structure-activity relationship and trypanocidal activity of pyrazole-imidazoline and new pyrazole-tetrahydropyrimidine hybrids as promising chemotherapeutic agents for Chagas disease

Monteiro, Maria Eduarda; Lechuga, Guilherme Curty; Lara, L.S.; Souto, Bernardo A.; Viganó, M.G.; Bourguignon, Saulo Cabral; Calvet, Cláudia M.; Oliveira, Francisco Odencio Rodrigues de; Alves, Carlos Roberto; Souza-Silva, Franklin; Santos, Maurício Silva dos; Pereira, Mirian Cláudia de Souza

doi:10.1016/j.ejmech.2019.111610

Cited by 22 publications

(7 citation statements)

References 51 publications

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“…Trypomastigote protein extracts (Dm28c-Luc; 10 8 parasites/mL) were obtained as previously described [ 30 ]. The cysteine protease activity of the total protein extracts (5 µg) was measured using the reaction buffer (CH 3 COONa 10 mM, pH 5.0 containing 1 mM DTT), in the presence of the fluorogenic peptide substrate (60 μM of 7-Amino-4-Methylcoumarin hydrochloride), CBZ-L-Phenylalanyl-l-Arginine amide (Z -FR-AMC), and serial dilutions of pyrazole-thiazolines derivatives (100–6.25 µM).…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, potent trypanocidal activity was evidenced by N -ethylurea pyrazole derivatives against T. brucei and T. cruzi , drastically reducing the parasitic burden in experimental acute infection by T. cruzi [ 29 ]. Also, we have recently reported the trypanocidal activity of pyrazole-imidazoline derivatives, showing low mammalian cell toxicity, and a prediction of good oral bioavailability by in silico analysis of physicochemical and ADMET properties [ 30 ]. The promising analogues bind by hydrogen bond and hydrophobic interactions to the active site of cruzipain, and significantly inhibit cysteine protease activity.…”

Section: Introductionmentioning

confidence: 99%

“…The promising analogues bind by hydrogen bond and hydrophobic interactions to the active site of cruzipain, and significantly inhibit cysteine protease activity. These derivatives have been used by our research group as a hit system to synthesize new compounds through rational optimization, including ring bioisosterism, functional group interconversion, and functional group removal [ 30 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…In 2015, researchers discovered the effectiveness of heterocyclic hybrids containing a pyrazole moiety in combating Leishmania aethiopica [ 50 ]. In turn, in 2019, the effectiveness of pyrazole derivatives against Trypanosoma cruzi was proven [ 51 ].…”

Section: New Compounds With Potential Antiparasitic Activitymentioning

confidence: 99%

The Current Directions of Searching for Antiparasitic Drugs

2022

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Parasitic diseases are still a huge problem for mankind. They are becoming the main cause of chronic diseases in the world. Migration of the population, pollution of the natural environment, and climate changes cause the rapid spread of diseases. Additionally, a growing resistance of parasites to drugs is observed. Many research groups are looking for effective antiparasitic drugs with low side effects. In this work, we present the current trends in the search for antiparasitic drugs. We report known drugs used in other disease entities with proven antiparasitic activity and research on new chemical structures that may be potential drugs in parasitic diseases. The described investigations of antiparasitic compounds can be helpful for further drug development.

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“…Several studies have shown the potential pharmacological effects of nitrogen-containing five-membered heterocycles. Pyrazole-based compounds have been reported as important small molecules in drug discovery for NTDs (Bekhit et al, 2015;Monteiro et al, 2019). For instance, Bekhit and coworkers in 2015 reported the antileishmanial activity of heterocycle hybrids containing the pyrazole moiety on Leishmania aethiopica ( Figure 1A), whereas Monteiro and coworkers in 2019 reported the trypanocidal activity of pyrazole derivatives on T. cruzi ( Figure 1B).…”

Section: Introductionmentioning

confidence: 99%

Antiparasitic Behavior of Trifluoromethylated Pyrazole 2-Amino-1,3,4-thiadiazole Hybrids and Their Analogues: Synthesis and Structure-Activity Relationship

et al. 2020

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A series of trifluoromethylated pyrazole thiosemicarbazone, trifluromethylated pyrazole isothiosemicarbazone, and trifluoromethylated pyrazole 2-amino-1,3,4-thiadiazole hybrids were synthesized and evaluated in vitro against the promastigote form of Leishmania amazonensis and the epimastigote form of Trypanosoma cruzi, the pathogens causing the neglected tropical diseases leishmaniasis and Chagas disease, respectively. The results show the potential of these compounds regarding their antiparasitic properties. Studies on the structure-activity relationship demonstrated that compounds containing a bulky group at the para position of the phenyl ring attached to the 5-position of the pyrazole core had better antiparasitic effects. Among the substituents attached at the 3-position of the pyrazole ring, the insertion of the 2-amino-1,3,4thiadiazole nucleus led to the most potent compounds compared to the thiosemicarbazone derivative.

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Synthesis, structure-activity relationship and trypanocidal activity of pyrazole-imidazoline and new pyrazole-tetrahydropyrimidine hybrids as promising chemotherapeutic agents for Chagas disease

Cited by 22 publications

References 51 publications

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

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

The Current Directions of Searching for Antiparasitic Drugs

Antiparasitic Behavior of Trifluoromethylated Pyrazole 2-Amino-1,3,4-thiadiazole Hybrids and Their Analogues: Synthesis and Structure-Activity Relationship

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