RESUMEN
Taurine (2-aminoethanesulfonic acid) is a non-protein ß-amino acid essential for cellular homeostasis, with antioxidant, anti-inflammatory, and cytoprotective properties that are crucial for life maintenance. This study aimed to evaluate the effects of taurine administration on hippocampal neurogenesis, neuronal preservation, or reverse damage in rats exposed to forced ethanol consumption in an animal model. Wistar rats were treated with ethanol (EtOH) for a 28-day period (5% in the 1st week, 10% in the 2nd week, and 20% in the 3rd and 4th weeks). Two taurine treatment protocols (300 mg/kg i.p.) were implemented: one during ethanol consumption to analyze neuroprotection, and another after ethanol consumption to assess the reversal of ethanol-induced damage. Overall, the results demonstrated that taurine treatment was effective in protecting against deficits induced by ethanol consumption in the dentate gyrus. The EtOH+TAU group showed a significant increase in cell proliferation (145.8%) and cell survival (54.0%) compared to the EtOH+Sal group. The results also indicated similar effects regarding the reversal of ethanol-induced damage 28 days after the cessation of ethanol consumption. The EtOH+TAU group exhibited a significant increase (41.3%) in the number of DCX-immunoreactive cells compared to the EtOH+Sal group. However, this amino acid did not induce neurogenesis in the tissues of healthy rats, implying that its activity may be contingent upon post-injury stimuli.
Asunto(s)
Proteína Doblecortina , Etanol , Hipocampo , Neurogénesis , Fármacos Neuroprotectores , Ratas Wistar , Taurina , Animales , Taurina/farmacología , Neurogénesis/efectos de los fármacos , Masculino , Fármacos Neuroprotectores/farmacología , Ratas , Hipocampo/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Giro Dentado/efectos de los fármacos , Neuronas/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
Chagas disease (CD) is a parasitic disease endemic in several developing countries. According to the World Health Organization, approximately 6-8 million people worldwide are inflicted by CD. The scarcity of new drugs, mainly for the chronic phase, is the main reason for treatment limitation in CD. Therefore, there is an urgent need to discover new targets for which new therapeutical agents could be developed. Cruzain cysteine protease (CCP) is a promising alternative because this enzyme exhibits pleiotropic effects by acting as a virulence factor, modulating host immune cells, and interacting with host cells. This systematic review was conducted to discover new compounds that act as cruzain inhibitors, and their effects in vitro were studied through enzymatic assays and molecular docking. Additionally, the advances and perspectives of these inhibitors are discussed. These findings are expected to contribute to medicinal chemistry in view of the design of new, safe, and efficacious inhibitors against Trypanosoma cruzi CCP detected in the last decade (2013-2022) to provide scaffolds for further optimization, aiming toward the discovery of new drugs.
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Histone deacetylases (HDAC) are epigenetic enzymes responsible for repressing gene expression through the deacetylation of histone lysine residues. Therefore, inhibition of HDACs has become an interesting approach for the treatment of several diseases, including cancer, hematology, neurodegenerative, immune diseases, bacterial infections, and more. Resveratrol (RVT) has pleiotropic effects, including pan-inhibition of HDAC isoforms; however, its ability to interfere with membranes requires additional optimization to eliminate nonspecific and off-target effects. Thus, to explore RVT as a scaffold, we designed a series of novel HDAC-1 and -2 inhibitors containing the 2-aminobenzamide subunit. Using molecular modeling, all compounds, except unsaturated compounds (4) and (7), exhibited a similar mode of interaction at the active sites of HDAC 1 and 2. The docking score values obtained from the study ranged from -12.780 to -10.967 Kcal/mol. All compounds were synthesized, with overall yields ranging from 33% to 67.3%. In an initial screening, compounds (4), (5), (7), and (20)-(26), showed enzymatic inhibitory effects ranging from 1 to 96% and 6 to 93% against HDAC-1 and HDAC-2, respectively. Compound (5), the most promising HDAC inhibitor in this series, was selected for IC50 assays, resulting in IC50 values of 0.44 µM and 0.37 µM against HDAC-1 and HDAC-2, respectively. In a panel of selectivity against HDACs 3-11, compound (5) presented selectivity towards Class I, mainly HDAC-1, 2, and 3. All compounds exhibited suitable physicochemical and ADMET properties as determined using in silico simulations. In conclusion, the optimization of the RVT structure allows the design of selective HDAC inhibitors, mainly targeting HDAC-1 and HDAC-2 isoforms.
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Chagas disease (CD) is a neglected protozoan infection caused by Trypanosoma cruzi, which affects about 7 million people worldwide. There are two available drugs in therapeutics, however, they lack effectiveness for the chronic stage-characterized mainly by cardiac (i.e., cardiomyopathy) and digestive manifestations (i.e., megaesophagus, megacolon). Due to the involvement of the immuno-inflammatory pathways in the disease's progress, compounds exhibiting antioxidant and anti-inflammatory activity seem to be effective for controlling some clinical manifestations, mainly in the chronic phase. Resveratrol (RVT) and curcumin (CUR) are natural compounds with potent antioxidant and anti-inflammatory properties and their cardioprotective effect have been proposed to have benefits to treat CD. Such effects could decrease or block the progression of the disease's severity. The purpose of this systematic review is to analyze the effectiveness of RVT and CUR in animal and clinical research for the treatment of CD. The study was performed according to PRISMA guidelines and it was registered on PROSPERO (CDR42021293495). The results did not find any clinical study, and the animal research was analyzed according to the SYRCLES risk of bias tools and ARRIVE 2.0 guidelines. We found 9 eligible reports in this study. We also discuss the potential RVT and CUR derivatives for the treatment of CD as well.
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Thiazoles, triazoles, and thiosemicarbazones function as efficient scaffolds in compounds for the treatment of several illnesses, including cancers. In this review article, we have demonstrated various studies involving these three pharmacophore classes (thiazoles, triazoles, and thiosemicarbazones) in medicinal chemistry over the last decade (2011-2021) with a focus on MCF-7 adenocarcinoma breast cancer cells. Our objective is to facilitate drug discovery of novel chemotherapeutic agents by detailing anti-proliferative compounds.
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Adenocarcinoma , Antineoplásicos , Neoplasias de la Mama , Tiosemicarbazonas , Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Desarrollo de Medicamentos , Femenino , Humanos , Tiazoles/química , Tiazoles/farmacología , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Triazoles/química , Triazoles/farmacologíaRESUMEN
Scaffolds of metal-based compounds can act as pharmacophore groups in several ligands to treat various diseases, including tropical infectious diseases (TID). In this review article, we investigate the contribution of these moieties to medicinal inorganic chemistry in the last seven years against TID, including American trypanosomiasis (Chagas disease), human African trypanosomiasis (HAT, sleeping sickness), leishmania, and malaria. The most potent metal-based complexes are displayed and highlighted in figures, tables and graphics; according to their pharmacological activities (IC50 > 10µM) against Trypanosomatids and Plasmodium spp parasites. We highlight the current progresses and viewpoints of these metal-based complexes, with a specific focus on drug discovery.
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Enfermedad de Chagas , Parásitos , Plasmodium , Trypanosoma cruzi , Tripanosomiasis Africana , Animales , Enfermedad de Chagas/tratamiento farmacológico , Descubrimiento de Drogas , Humanos , Tripanosomiasis Africana/tratamiento farmacológicoRESUMEN
Abstract The chemical hydroxymethylation of the antimicrobial nitrofurazone leads to the prodrug NFOH, also increases the anti-T. cruzi activities (in vitro and in vivo), as well as showed non-genotoxic (Ames and micronucleus assays). In the present study, we assessed the anti-T. cruzi effect of the NFOH In vivo - in acute Swiss and C57Bl/6 experimental Chagas models. The treatment started at 5 days post-infection during 20 consecutive days (orally, once day, 150mg/kg), and the parasitaemia as well as histopathology analysis were performed. In both experimental murine models, NFOH was able to reduce parasitemia blood avoiding parasitic reactivation, during immunosuppression period (dexamethasone 5mg/kg, 14 days), in 100% of the mice, and decrease tissue parasite nests, demonstrating absence of amastigote forms in all organs (100%) analyzed, data similar to benznidazole (BZN). Therefore, the results shown here pointing to the NFOH as promising compound for further preclinical studies, being a high potential drug to effective and safe chemotherapy to Chagas disease.
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Animales , Masculino , Ratas , Trypanosoma cruzi/patogenicidad , Infecciones/inducido químicamente , Técnicas In Vitro/métodos , Dexametasona/efectos adversos , Preparaciones Farmacéuticas/administración & dosificación , Enfermedad de Chagas/clasificaciónRESUMEN
Hydroxymethylnitrofurazone (NFOH) is a therapeutic candidate for Chagas disease (CD). It has negligible hepatotoxicity in a murine model compared to the front-line drug benznidazole (BZN). Here, using Trypanosoma cruzi strains that express bioluminescent and/or fluorescent reporter proteins, we further investigated the in vitro and in vivo activity of NFOH to define whether the compound is trypanocidal or trypanostatic. The in vitro activity was assessed by exploiting the fluorescent reporter strain using wash-out assays and real-time microscopy. For animal experimentation, BALB/c mice were inoculated with the bioluminescent reporter strain and assessed by highly sensitive in vivo and ex vivo imaging. Cyclophosphamide treatment was used to promote parasite relapse in the chronic stage of infection. Our data show that NFOH acts by a trypanostatic mechanism, and that it is more active than BZN in vitro against the infectious trypomastigote form of Trypanosoma cruzi. We also found that it is more effective at curing experimental infections in the chronic stage, compared with the acute stage, a feature that it shares with BZN. Therefore, given its reduced toxicity, enhanced anti-trypomastigote activity, and curative properties, NFOH can be considered as a potential therapeutic option for Chagas disease, perhaps in combination with other trypanocidal agents.
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Enfermedad de Chagas/tratamiento farmacológico , Nitrofurazona/análogos & derivados , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/patogenicidad , Animales , Enfermedad de Chagas/parasitología , Femenino , Mediciones Luminiscentes , Ratones , Ratones Endogámicos BALB C , Nitrofurazona/farmacología , Nitrofurazona/uso terapéuticoRESUMEN
Metal-based drugs are privileged motifs that act as primary pharmacophores in bioactive compounds for various diseases, including tuberculosis (TB). This potentially life-threatening and extremely contagious infectious disease is caused by Mycobacterium tuberculosis (Mtb). In 2018, TB infected about 10 million people and caused 1.2 million deaths worldwide. A large number of ligands are promising scaffolds in drug design, including heterocyclic, phosphines, schiff bases, thio and semicarbazones, aliphatic amines, cyclopalladated, cyanometallates and miscellaneous. Moreover, several metal-based complexes have been studied for the treatment of numerous illnesses, including infectious diseases. To contribute to drug design, we identified the metal-based organometallic complexes against Mtb. Thus, in this review article, we analysed the recent contributions of metal-based scaffolds for design of new anti-Mtb drugs in the last decade (2011-2020). Besides, metal-based approaches will be presented in order to find out new antitubercular agents.
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Antituberculosos/farmacología , Descubrimiento de Drogas , Mycobacterium tuberculosis/efectos de los fármacos , Compuestos Organometálicos/farmacología , Animales , Antituberculosos/síntesis química , Antituberculosos/química , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/químicaRESUMEN
Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), is the largest pandemic in modern history with very high infection rates and considerable mortality. The disease, which emerged in China's Wuhan province, had its first reported case on December 29, 2019, and spread rapidly worldwide. On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic and global health emergency. Since the outbreak, efforts to develop COVID-19 vaccines, engineer new drugs, and evaluate existing ones for drug repurposing have been intensively undertaken to find ways to control this pandemic. COVID-19 therapeutic strategies aim to impair molecular pathways involved in the virus entrance and replication or interfere in the patients' overreaction and immunopathology. Moreover, nanotechnology could be an approach to boost the activity of new drugs. Several COVID-19 vaccine candidates have received emergency-use or full authorization in one or more countries, and others are being developed and tested. This review assesses the different strategies currently proposed to control COVID-19 and the issues or limitations imposed on some approaches by the human and viral genetic variability.
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Chagas disease is a protozoan infection that was identified over a century ago. No drugs are available to treat the indeterminate and determinate chronic phases of the disease. Success of a drug design is dependent on correct biological evaluation. Concerning new drug designs for Chagas disease, it is essential to first identify the most effective, existing, experimental chronic protocols that can be used for comparison purposes. Here, we present a literature review regarding experimental models with chronic Chagas disease to evaluate the efficacy of benznidazole (BZN). We searched literature published in PubMed and Web of Science databases, using these keywords: animal model, BZN, Chagas disease, T. cruzi, and chronic phase, with no timeframe limitations. We excluded articles involving acute phase animal models and/or those without BZN treatment. The selected studies were conducted using different BZN concentrations (10mg-100mg) involving several different periods (5-70 days). Concentrations and durations of use are directly related to side effects, but do not prevent chronic tissue lesions. BZN use during the late/chronic phases of Chagas disease is unable to eliminate amastigote forms present in infected tissues. This study suggests the administration of a lower BZN concentration (<100mg/kg/day) during the chronic phase of the animal model, as this had been reported to result in fewer side effects.
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Enfermedad de Chagas/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Nitroimidazoles/administración & dosificación , Tripanocidas/administración & dosificación , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , RatonesRESUMEN
Abstract Chagas disease is a protozoan infection that was identified over a century ago. No drugs are available to treat the indeterminate and determinate chronic phases of the disease. Success of a drug design is dependent on correct biological evaluation. Concerning new drug designs for Chagas disease, it is essential to first identify the most effective, existing, experimental chronic protocols that can be used for comparison purposes. Here, we present a literature review regarding experimental models with chronic Chagas disease to evaluate the efficacy of benznidazole (BZN). We searched literature published in PubMed and Web of Science databases, using these keywords: animal model, BZN, Chagas disease, T. cruzi, and chronic phase, with no timeframe limitations. We excluded articles involving acute phase animal models and/or those without BZN treatment. The selected studies were conducted using different BZN concentrations (10mg-100mg) involving several different periods (5-70 days). Concentrations and durations of use are directly related to side effects, but do not prevent chronic tissue lesions. BZN use during the late/chronic phases of Chagas disease is unable to eliminate amastigote forms present in infected tissues. This study suggests the administration of a lower BZN concentration (<100mg/kg/day) during the chronic phase of the animal model, as this had been reported to result in fewer side effects.
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Animales , Tripanocidas/administración & dosificación , Enfermedad de Chagas/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Nitroimidazoles/administración & dosificación , Enfermedad Crónica , Modelos Animales de Enfermedad , RatonesRESUMEN
Fetal hemoglobin (HbF) induction by hydroxyurea (HU) therapy is associated with decreased morbidity and mortality in sickle cell anemia (SCA) patients, but not all patients respond to or tolerate HU. This provides a rationale for developing novel HbF inducers to treat SCA. Thalidomide analogs have the ability to induce HbF production while inhibiting the release of tumor necrosis factor-alpha. Molecular hybridization of HU and thalidomide was used to synthesize 3- (1,3-dioxoisoindolin-2-yl) benzyl nitrate (compound 4C). In this study, we show that compound 4C increases HbF production in a transgenic SCA mouse model and reduces the production of pro-inflammatory cytokines by SCA mouse monocytes cultured ex vivo. Therefore, compound 4C is a novel drug designed to treat SCA with a unique combination of HbF-inducing and anti-inflammatory properties.
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Anemia de Células Falciformes/tratamiento farmacológico , Citocinas/metabolismo , Hemoglobina Fetal/biosíntesis , Hidroxiurea , Talidomida , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/metabolismo , Anemia de Células Falciformes/patología , Animales , Citocinas/genética , Modelos Animales de Enfermedad , Hemoglobina Fetal/genética , Hidroxiurea/análogos & derivados , Hidroxiurea/síntesis química , Hidroxiurea/química , Hidroxiurea/farmacología , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Ratones , Ratones Noqueados , Talidomida/análogos & derivados , Talidomida/síntesis química , Talidomida/química , Talidomida/farmacologíaRESUMEN
Resveratrol (RVT) is one of the main natural compounds studied worldwide due to its potential therapeutic use in the treatment of many diseases, including cancer, diabetes, cardiovascular diseases, neurodegenerative diseases and metabolic disorders. Nevertheless, the mechanism of action of RVT in all of these conditions is not completely understood, as it can modify not only biochemical pathways but also epigenetic mechanisms. In this paper, we analyze the biological activities exhibited by RVT with a focus on the epigenetic mechanisms, especially those related to DNA methyltransferase (DNMT), histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1).
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Metilación de ADN/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Estilbenos/farmacología , Acetilación , Animales , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Metilasas de Modificación del ADN/antagonistas & inhibidores , Metilasas de Modificación del ADN/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Histona Demetilasas/antagonistas & inhibidores , Histona Demetilasas/metabolismo , Histonas/metabolismo , Humanos , Resveratrol , Transducción de Señal/efectos de los fármacosRESUMEN
Resveratrol (RVT) is a stilbene with a protective effect on the cardiovascular system; however, drawbacks including low bioavailability and fast metabolism limit its efficacy. In this work we described new resveratrol derivatives with nitric oxide (NO) release properties, ability to inhibit platelet aggregation and in vivo antithrombotic effect. Compounds (4a-f) were able to release NO in vitro, at levels ranging from 24.1% to 27.4%. All compounds (2a-f and 4a-f) have exhibited platelet aggregation inhibition using as agonists ADP, collagen and arachidonic acid. The most active compound (4f) showed reduced bleeding time compared to acetylsalicylic acid (ASA) and protected up to 80% against in vivo thromboembolic events. These findings suggest that hybrid resveratrol-furoxan (4f) is a novel lead compound able to prevent platelet aggregation and thromboembolic events.
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Fibrinolíticos/farmacología , Hidrazonas/farmacología , Donantes de Óxido Nítrico/farmacología , Oxadiazoles/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Adenosina Difosfato/farmacología , Animales , Ácido Araquidónico/farmacología , Aspirina/farmacología , Tiempo de Sangría , Colágeno/farmacología , Fibrinolíticos/síntesis química , Hidrazonas/síntesis química , Dinitrato de Isosorbide/farmacología , Masculino , Ratones , Donantes de Óxido Nítrico/síntesis química , Nitritos/análisis , Oxadiazoles/síntesis química , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/síntesis química , Ratas WistarRESUMEN
Tuberculosis is one of the leading causes of morbidity and mortality worldwide. Current treatment has several challenges, such as multi-drug resistance, extensively drug-resistance and HIV co-infection. Problems related to patients, treatment and health care system also contribute negatively to this panel. This review summarizes the main obstacles causing in the treatment of tuberculosis and discusses several strategies to improve the treatment.
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Antituberculosos/uso terapéutico , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Tuberculosis/epidemiología , Animales , Antituberculosos/farmacología , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Resultado del Tratamiento , Tuberculosis/diagnósticoRESUMEN
Tuberculosis (TB) is an infectious disease caused by bacterium of the Mycobacterium genus, mainly by Mycobacterium tuberculosis (MTB). The World Health Organization aims to substantially reduce the number of cases in the coming years; however, the increased number of multidrug-resistant (MDR) and extremely drug-resistant (XDR) forms of the bacterium and the lack of treatment for latent tuberculosis are challenges to be overcome. In this review, we have identified the most potent compounds described in the literature during recent years with MIC values < 7 µM, low toxicity and a high selective index. In addition, emerging targets in MTB are presented to provide new perspectives for the discovery of new antitubercular drugs. This review aims to summarize the current advances in and promote insights into antitubercular drug discovery.
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Antituberculosos/farmacología , Descubrimiento de Drogas , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Animales , Antituberculosos/química , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium tuberculosis/metabolismo , Tuberculosis/microbiologíaRESUMEN
Helicobacter pylori (H. pylori) is one of the leading causes of gastric diseases such as chronic gastritis, peptic ulcer, and gastric adenocarcinoma. The current treatment of H. pylori infection with antibiotics and proton pump inhibitors has several limitations, including poor adherence and intrinsic patient-related factors, drug resistance, and the absence of adequate treatments. This review summarizes the current therapeutic approaches to eradicating H. pylori, the difficulties associated with its treatment, and several new perspectives aimed at improving existing treatment strategies.
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Adenocarcinoma/prevención & control , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/efectos de los fármacos , Neoplasias Gástricas/prevención & control , Antibacterianos/administración & dosificación , Quimioterapia Combinada , Femenino , Gastritis/tratamiento farmacológico , Gastritis/etiología , Helicobacter pylori/aislamiento & purificación , Humanos , Masculino , Úlcera Péptica/tratamiento farmacológico , Úlcera Péptica/etiología , Pronóstico , Inhibidores de la Bomba de Protones/uso terapéutico , Medición de Riesgo , Resultado del TratamientoRESUMEN
Plasmodium vivax is the most prevalent of the five species causing malaria in humans. The current available treatment for P. vivax malaria is limited and unsatisfactory due to at least two drawbacks: the undesirable side effects of primaquine (PQ) and drug resistance to chloroquine. Phenylalanine-alanine-PQ (Phe-Ala-PQ) is a PQ prodrug with a more favorable pharmacokinetic profile compared to PQ. The toxicity of this prodrug was evaluated in in vitro assays using a human hepatoma cell line (HepG2), a monkey kidney cell line (BGM), and human red blood cells deficient in the enzyme glucose-6-phosphate-dehydrogenase (G6PD). In addition, in vivo toxicity assays were performed with rats that received multiple doses of Phe-Ala-PQ to evaluate biochemical, hematological, and histopathological parameters. The activity was assessed by the inhibition of the sporogonic cycle using a chicken malaria parasite. Phe-Ala-PQ blocked malaria transmission in Aedes mosquitoes. When compared with PQ, it was less cytotoxic to BGM and HepG2 cells and caused less hemolysis of G6PD-deficient red blood cells at similar concentrations. The prodrug caused less alteration in the biochemical parameters than did PQ. Histopathological analysis of the liver and kidney did show differences between the control and Phe-Ala-PQ-treated groups, but they were not statistically significant. Taken together, the results highlight the prodrug as a novel lead compound candidate for the treatment of P. vivax malaria and as a blocker of malaria transmission.