Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

Scarim, Cauê Benito; Chin, Chung Man

doi:10.2174/1386207322666191010144111

Cited by 7 publications

(5 citation statements)

References 79 publications

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“…Considering the above and the fact the pharmaceutical industry does not invest in research for NTDs, it is great importance to nd new alternatives for the treatment of trypanosomiasis. For this reason, many academic research groups are searching for new trypanosomicidal therapeutic alternatives through the design and synthesis of small molecules [5,6].…”

Section: Introductionmentioning

confidence: 99%

Expanding the chemical space of aryloxy-naphthoquinones as potential anti-Chagasic agents: synthesis and trypanosomicidal activity

et al. 2021

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In continuation our effort to research the chemical space of aryloxy-naphthoquinones as potential anti-Chagas agents, we synthesized nine derivatives and these compounds were evaluated in vitro against the epimastigote and trypomastigote forms of Mexican strains of Trypanosoma cruzi (T. cruzi). Most of these derivatives are highly active against epimastigote forms (IC 50 < 1.0 µM) compared to the reference drug benznidazole (Bzn). Then these were evaluated on trypomastigotes, which is showing better potency results than Bzn for compounds 3b and 3g. In addition, the cytotoxicity of these compounds was determined on the murine macrophage cell line J774. 3b and 3i were the most selective compounds against NINOA trypomastigote and INC-5 epimastigote forms, respectively. Further these compounds also have good oral bioavailability according to theoretical predictions. Finally, we were able to determine optimal substitution patterns using pharmacophoric models. All these results are provided very useful structural information to continue our designing of naphthoquinone derivatives against T. cruzi.

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Section: Introductionmentioning

confidence: 99%

Expanding the chemical space of aryloxy-naphthoquinones as potential anti-Chagasic agents: synthesis and trypanosomicidal activity

et al. 2021

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“…Lack of uniform methodology also limits our ability to generalize the findings. The advent of automated high-content imaging [62][63][64][65], as an alternative for screening of anti-T. cruzi drugs, allows for large-scale experiments, in particular for the intracellular amastigote model which was recommended to be used as gold standard by the Drugs for Neglected Diseases initiative (DNDi) [62]. This method, which displays increased sensitivity when compared with colorimetric and fluorometric assays [38,62], will allow to screen large compound libraries for activity against standard T. cruzi strains and field isolates representative of the different DTUs.…”

Section: Discussionmentioning

confidence: 99%

In vitro susceptibility of Trypanosoma cruzi discrete typing units (DTUs) to benznidazole: A systematic review and meta-analysis

et al. 2021

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Background Chagas disease, a neglected tropical disease endemic to Latin America caused by the parasite Trypanosoma cruzi, currently affects 6–7 million people and is responsible for 12,500 deaths each year. No vaccine exists at present and the only two drugs currently approved for the treatment (benznidazole and nifurtimox), possess serious limitations, including long treatment regimes, undesirable side effects, and frequent clinical failures. A link between parasite genetic variability and drug sensibility/efficacy has been suggested, but remains unclear. Therefore, we investigated associations between T. cruzi genetic variability and in vitro benznidazole susceptibility via a systematic article review and meta-analysis. Methodology/Principal findings In vitro normalized benznidazole susceptibility indices (LC50 and IC50) for epimastigote, trypomastigote and amastigote stages of different T. cruzi strains were recorded from articles in the scientific literature. A total of 60 articles, which include 189 assays, met the selection criteria for the meta-analysis. Mean values for each discrete typing unit (DTU) were estimated using the meta and metaphor packages through R software, and presented in a rainforest plot. Subsequently, a meta-regression analysis was performed to determine differences between estimated mean values by DTU/parasite stage/drug incubation times. For each parasite stage, some DTU mean values were significantly different, e.g. at 24h of drug incubation, a lower sensitivity to benznidazole of TcI vs. TcII trypomastigotes was noteworthy. Nevertheless, funnel plots detected high heterogeneity of the data within each DTU and even for a single strain. Conclusions/Significance Several limitations of the study prevent assigning DTUs to different in vitro benznidazole sensitivity groups; however, ignoring the parasite’s genetic variability during drug development and evaluation would not be advisable. Our findings highlight the need for establishment of uniform experimental conditions as well as a screening of different DTUs during the optimization of new drug candidates for Chagas disease treatment.

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“…However, only two drugs, benznidazole and nifurtimox, have been approved for treating the infection, both of which are frequently associated with unpleasant side effects and low effectiveness [ 111 , 112 ]. Therefore, there is a requirement to discover new compounds with trypanocidal activity that are safer and more effective than the current drugs [ 113 , 114 ].…”

Section: Trypanosoma Cruzi Carbonic Anhydrase (Ca)mentioning

confidence: 99%

Targeting Metalloenzymes: The “Achilles’ Heel” of Viruses and Parasites

Moianos,

Prifti,

Makri

et al. 2023

Pharmaceuticals

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Metalloenzymes are central to the regulation of a wide range of essential viral and parasitic functions, including protein degradation, nucleic acid modification, and many others. Given the impact of infectious diseases on human health, inhibiting metalloenzymes offers an attractive approach to disease therapy. Metal-chelating agents have been expansively studied as antivirals and antiparasitics, resulting in important classes of metal-dependent enzyme inhibitors. This review provides the recent advances in targeting the metalloenzymes of viruses and parasites that impose a significant burden on global public health, including influenza A and B, hepatitis B and C, and human immunodeficiency viruses as well as Trypanosoma brucei and Trypanosoma cruzi.

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Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

Cited by 7 publications

References 79 publications

Expanding the chemical space of aryloxy-naphthoquinones as potential anti-Chagasic agents: synthesis and trypanosomicidal activity

Expanding the chemical space of aryloxy-naphthoquinones as potential anti-Chagasic agents: synthesis and trypanosomicidal activity

In vitro susceptibility of Trypanosoma cruzi discrete typing units (DTUs) to benznidazole: A systematic review and meta-analysis

Targeting Metalloenzymes: The “Achilles’ Heel” of Viruses and Parasites

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