RESUMEN
Novel saturated 6-(4'-aryloxy phenyl) vinyl 1,2,4-trioxanes 12a(1-3)-12d(1-3) and 13a(1-3)-13d(1-3) have been designed and synthesized, in one single step from diimide reduction of 11a(1-3)-11d(1-3). All the newly synthesized trioxanes were evaluated for their antimalarial activity against multi-drug resistant Plasmodium yoelii nigeriensis via oral route. Cyclopentane-based trioxanes 12b1, 12c1 and 12d1, provided 100 % protection to the infected mice at 24 mg/kg × 4 days. The most active compound of the series, trioxane 12b1, provided 100 % protection even at 12 mg/kg × 4 days and 60 % protection at 6 mg/kg × 4 days. The currently used drug, ß-arteether provides only 20 % protection at 24 mg/kg × 4 days.
Asunto(s)
Antimaláricos , Resistencia a Múltiples Medicamentos , Compuestos Heterocíclicos , Malaria , Plasmodium yoelii , Animales , Plasmodium yoelii/efectos de los fármacos , Antimaláricos/farmacología , Antimaláricos/química , Antimaláricos/síntesis química , Ratones , Administración Oral , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Malaria/tratamiento farmacológico , Relación Estructura-Actividad , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Estructura Molecular , Modelos Animales de Enfermedad , Pruebas de Sensibilidad ParasitariaRESUMEN
The increasing resistance of various malarial parasite strains to drugs has made the production of a new, rapid-acting, and efficient antimalarial drug more necessary, as the demand for such drugs is growing rapidly. As a major global health concern, various methods have been implemented to address the problem of drug resistance, including the hybrid drug concept, combination therapy, the development of analogues of existing medicines, and the use of drug resistance reversal agents. Artemisinin and its derivatives are currently used against multidrug- resistant P. falciparum species. However, due to its natural origin, its use has been limited by its scarcity in natural resources. As a result, finding a substitute becomes more crucial, and the peroxide group in artemisinin, responsible for the drugs biological action in the form of 1,2,4-trioxane, may hold the key to resolving this issue. The literature suggests that 1,2,4-trioxanes have the potential to become an alternative to current malaria drugs, as highlighted in this review. This is why 1,2,4-trioxanes and their derivatives have been synthesized on a large scale worldwide, as they have shown promising antimalarial activity in vivo and in vitro against Plasmodium species. Consequently, the search for a more convenient, environment friendly, sustainable, efficient, and effective synthetic pathway for the synthesis of 1,2,4-trioxanes continues. The aim of this work is to provide a comprehensive analysis of the synthesis and mechanism of action of 1,2,4-trioxanes. This systematic review highlights the most recent summaries of derivatives of 1,2,4-trioxane compounds and dimers with potential antimalarial activity from January 1988 to 2023.
Asunto(s)
Antimaláricos , Artemisininas , Compuestos Heterocíclicos , Artemisininas/farmacología , Compuestos Heterocíclicos/farmacología , Plasmodium falciparumRESUMEN
Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against Leishmania parasites. This study reports the synthesis and structure of trioxolane-pyrazole (OZ1, OZ2) and tetraoxane-pyrazole (T1, T2) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for in vitro antileishmanial activity against promastigotes of L. tropica and L. infantum, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of L. infantum. Trioxolane-pyrazole hybrids OZ1 and OZ2 exhibited some activity against Leishmania promastigotes, while tetraoxane-pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound OZ1â¢HCl was the most active against both strains of Leishmania. Such finding was corroborated by the results obtained in assessments of the L. infantum amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide-pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of Leishmania. Our preliminary biological findings encourage further optimization of peroxide-pyrazole hybrids to identify a promising antileishmanial lead.
Asunto(s)
Antiprotozoarios , Leishmania infantum , Leishmania , Leishmaniasis , Tetraoxanos , Antiprotozoarios/química , Humanos , Leishmaniasis/tratamiento farmacológico , Pirazoles/química , Tetraoxanos/farmacología , Tetraoxanos/uso terapéuticoRESUMEN
Bridged aminoperoxides, for the first time, were investigated for the inâ vitro antimalarial activity against the chloroquine-resistant Plasmodium falciparum strain K1 and for their cytotoxic activities against immortalized human normal liver (LO2) and lung (BEAS-2B) cell lines as well as human liver (HepG2) and lung (A549) cancer cell lines. Aminoperoxides exhibit good cytotoxicity against lung A549 cancer cell line. Synthetic ozonides were shown to have high activity against the chloroquine-resistant P. falciparum. A cyclic voltammetry study of peroxides was performed, and most of the compounds did not show a direct correlation in oxidative capacity-activity. Peroxides were analyzed for ROS production to understand their mechanism of action. However, none of the compounds has an impact on ROS generation, suggesting that ozonides induce apoptosis in HepG2 cells through ROS-independent dysfunction pathway.
Asunto(s)
Antimaláricos , Antagonistas del Ácido Fólico , Tetraoxanos , Humanos , Antimaláricos/farmacología , Especies Reactivas de Oxígeno , Plasmodium falciparum , Peróxidos/farmacología , CloroquinaRESUMEN
1,2,4-trioxane is a pharmacophore, which possesses a wide spectrum of biological activities, including anticancer effects. In this study, the cytotoxic effect and anticancer mechanism of action of a set of 10 selected peroxides were investigated on five phenotypically different cancer cell lines (A549, A2780, HCT8, MCF7, and SGC7901) and their corresponding drug-resistant cancer cell lines. Among all peroxides, only 7 and 8 showed a better P-glycoprotein (P-gp) inhibitory effect at a concentration of 100 nM. These in vitro results were further validated by in silico docking and molecular dynamic (MD) studies, where compounds 7 and 8 exhibited docking scores of -7.089 and -8.196 kcal/mol, respectively, and remained generally stable in 100 ns during MD simulation. Further experiments revealed that peroxides 7 and 8 showed no significant effect on ROS accumulations and caspase-3 activity in A549 cells. Peroxides 7 and 8 were also found to decrease cell membrane potential. In addition, peroxides 7 and 8 were demonstrated to oxidize a flavin cofactor, possibly elucidating its mechanism of action. In conclusion, apoptosis induced by 1,2,4-trioxane was shown to undergo via a ROS- and caspase-3-independent pathway with hyperpolarization of cell membrane potential.
RESUMEN
Malaria is a life-threatening infectious disease caused by protozoal parasites belonging to the genus Plasmodium. It caused an estimated 405,000 deaths and 228 million malaria cases globally in 2018 as per the World Malaria Report released by World Health Organization (WHO) in 2019. Artemisinin (ART), a "Nobel medicine" and its derivatives have proven potential application in antimalarial drug discovery programs. In this review, antimalarial activity of the most active artemisinin derivatives modified at C-10/C-11/C-16/C-6 positions and synthetic peroxides (endoperoxides, 1,2,4-trioxolanes, 1,2,4-trioxanes, and 1,2,4,5-tetraoxanes) are systematically summarized. The developmental trend of ART derivatives, and cyclic peroxides along with their antimalarial activity and how the activity is affected by structural variations on different sites of the compounds are discussed. This compilation would be very useful towards scaffold hopping aimed at avoiding the unnecessary complexity in cyclic peroxides, and ultimately act as a handy resource for the development of potential chemotherapeutics against Plasmodium species.
Asunto(s)
Antimaláricos/farmacología , Artemisininas/farmacología , Descubrimiento de Drogas , Malaria/tratamiento farmacológico , Peróxidos/farmacología , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Artemisininas/síntesis química , Artemisininas/química , Humanos , Peróxidos/síntesis química , Peróxidos/químicaRESUMEN
Artemisinin and its analogs have shown potent anticancer activity in primary cancer cultures and cell lines by inhibiting cancer proliferation, metastasis, and angiogenesis. Despite its apparent compatibility to normal cells and low IC50 values in comparison to the commonly used anticancer drugs, the underlying mechanisms behind their cytotoxic effects are not yet fully understood. Surprisingly, the efficacy of synthetic 1,2,4-trioxanes against cancer has not been explored yet. Given the high antitumor activity of artemisinin dimers in comparison to their monomers, we report here the synthesis of simple 1,2,3-triazole conjugated 1,2,4-trioxanes and their potential antitumor activity by studying their inhibitory effect on osteopontin (OPN) expression in MDA-MB-435 breast cancer cells. It may be noted that despite being a strong marker to identify human tumor metastasis, no study on effect of artemisinin and its synthetic and semisynthetic derivatives on OPN expression has ever been studied. Although our initial studies did not notice any straight-line relationship between the number of trioxane units in a molecule to the extent of inhibition of OPN protein expression, we could observe better results in some cases in comparison to artemisinin. We have observed that artemisinin did not show appreciable OPN downregulation in MDA-MB-435 cancer cells, but dihydroartemisinin (DHA) and some synthetic 1,2,4-trioxane monomers and dimers showed downregulation of OPN expression. Therefore, these compounds may act as an anti-metastatic agent in controlling breast cancer cells metastasis.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Compuestos Heterocíclicos/farmacología , Osteopontina/antagonistas & inhibidores , Triazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Femenino , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Humanos , Estructura Molecular , Osteopontina/biosíntesis , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
A series of substituted 1,2,4-trioxanes were synthesized and evaluated for their antimalarial potential, in silico ADME properties and cytotoxicity on neuronal cell lines. Among the 15 synthesized substituted 1,2,4-trioxanes, two compounds (compound 15, IC50 = 25.71 nM; compound 21, IC50 = 19.6 nM) exhibited promising in vitro antimalarial potential comparable to those of the existing drugs chloroquine and artemisinin. Both of these compounds were found to be nontoxic up to 20 µM concentration in neuronal PC-12 cells. Compound 21 may serve as an optimized lead compound because of its less in vitro toxicity and lower probability to cross the blood brain barrier.
Asunto(s)
Antimaláricos/farmacología , Diseño de Fármacos , Compuestos Heterocíclicos/farmacología , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/síntesis química , Antimaláricos/química , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
A new series of ester analogues of artemisinin 8a-f, incorporating diphenylmethyl as pharmacologically privileged substructure, and 8g-j have been prepared and evaluated for their antimalarial activity against multidrug-resistant (MDR) Plasmodium yoelii nigeriensis in Swiss mice via oral route. These diphenylmethyl-based ester analogues 8a-f were found to be 2-4 folds more active than the antimalarial drugs ß-arteether 4 and artesunic acid 5. Ester 8a, the most active compound of the series, provided complete protection to the infected mice at 24 mg/kg × 4 days as well as 12 mg/kg × 4 days, respectively. In this model ß-arteether provided 100% and 20% protection at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Artemisininas/administración & dosificación , Artemisininas/farmacología , Resistencia a Múltiples Medicamentos , Ésteres/farmacología , Plasmodium yoelii/efectos de los fármacos , Administración Oral , Animales , Antimaláricos/administración & dosificación , Antimaláricos/química , Artemisininas/síntesis química , Artemisininas/química , Relación Dosis-Respuesta a Droga , Ésteres/administración & dosificación , Ésteres/química , Ratones , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
The present review describes the current status of synthetic five and six-membered cyclic peroxides such as 1,2-dioxolanes, 1,2,4-trioxolanes (ozonides), 1,2-dioxanes, 1,2-dioxenes, 1,2,4-trioxanes, and 1,2,4,5-tetraoxanes. The literature from 2000 onwards is surveyed to provide an update on synthesis of cyclic peroxides. The indicated period of time is, on the whole, characterized by the development of new efficient and scale-up methods for the preparation of these cyclic compounds. It was shown that cyclic peroxides remain unchanged throughout the course of a wide range of fundamental organic reactions. Due to these properties, the molecular structures can be greatly modified to give peroxide ring-retaining products. The chemistry of cyclic peroxides has attracted considerable attention, because these compounds are used in medicine for the design of antimalarial, antihelminthic, and antitumor agents.
RESUMEN
A novel series of 1,2,4-trioxanes were synthesized from 2H-pyrans via photooxidation, and their antiproliferative and growth factor inhibitory activity has been investigated across a variety of human cancer cell lines. Compounds 5k, 5l, 5s, 7a and 7c exhibited the highest activity and selectivity against a human leukemia (MV4-11) cell line (IC50 = 0.5 µM). Compound 5o showed the highest growth factor inhibitory activity against a melanoma (LOX-IMVI) cancer cell line (GI50 = 1.0 µM). A SAR study has confirmed the importance of the 1,2,4-trioxane unit as a pharmacophore for anticancer activity. The computer-assisted database analysis, COMPARE, has suggested that the compounds have unique mechanisms of actions that were different from those of known anticancer drugs. Some of the selected trioxanes were tested against the NF54 strain, albeit showing weak antiplasmodial activity. The molecular docking of trioxanes and hemin reveals that a short distance (1.30 Å) leads to their physical contact. The UV-vis spectroscopic analysis ensured the definite complexation between 1,2,4-trioxanes and hemin. The role of hemin-trioxane interaction in the hemin-induced oxidative damage has been studied using methylene blue as a substrate by UV-vis spectroscopy.