RESUMEN
The literature reports that thiazole and isatin nuclei present a range of biological activities, with an emphasis on anticancer activity. Therefore, our proposal was to make a series of compounds using the molecular hybridization strategy, which has been used by our research group, producing hybrid molecules containing the thiazole and isatin nuclei. After structural planning and synthesis, the compounds were characterized and evaluated in vitro against breast cancer cell lines (T-47D, MCF-7 and MDA-MB-231) and against normal cells (PBMC). The activity profile on membrane proteins involved in chemoresistance and tumorigenic signaling proteins was also evaluated. Among the compounds tested, the compounds 4c and 4a stood out with IC50 values of 1.23 and 1.39 µM, respectively, against the MDA-MB-231 cell line. Both compounds exhibited IC50 values of 0.45 µM for the MCF-7 cell line. Compounds 4a and 4c significantly decreased P-gp mRNA expression levels in MCF-7, 4 and 2 folds respectively. Regarding the impact on tumorigenic signaling proteins, compound 4a inhibited Akt2 in MDA-MB-231 and compound 4c inhibited the mRNA expression of VIM in MCF-7.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Isatina , Proteínas Proto-Oncogénicas c-akt , ARN Mensajero , Tiazoles , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Isatina/farmacología , Isatina/química , Isatina/síntesis química , Línea Celular Tumoral , ARN Mensajero/metabolismo , ARN Mensajero/genética , Tiazoles/farmacología , Tiazoles/química , Femenino , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Simulación del Acoplamiento Molecular , Células MCF-7 , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-ActividadRESUMEN
BACKGROUND: Chemoinformatics has several applications in the field of drug design, helping to identify new compounds against a range of ailments. Among these are Leishmaniasis, effective treatments for which are currently limited. OBJECTIVE: To construct new indole 2-aminothiophene molecules using computational tools and to test their effectiveness against Leishmania amazonensis (sp.). METHODS: Based on the chemical structure of thiophene-indol hybrids, we built regression models and performed molecular docking, and used these data as bases for design of 92 new molecules with predicted pIC50 and molecular docking. Among these, six compounds were selected for the synthesis and to perform biological assays (leishmanicidal activity and cytotoxicity). RESULTS: The prediction models and docking allowed inference of characteristics that could have positive influences on the leishmanicidal activity of the planned compounds. Six compounds were synthesized, one-third of which showed promising antileishmanial activities, with IC50 ranging from 2.16 and 2.97 µM (against promastigote forms) and 0.9 and 1.71 µM (against amastigote forms), with selectivity indexes (SI) of 52 and 75. CONCLUSION: These results demonstrate the ability of Quantitative Structure-Activity Relationship (QSAR)-based rational drug design to predict molecules with promising leishmanicidal potential, and confirming the potential of thiophene-indole hybrids as potential new leishmanial agents.
Asunto(s)
Antiprotozoarios/farmacología , Diseño de Fármacos , Indoles/farmacología , Leishmania/efectos de los fármacos , Tiofenos/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Indoles/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad Cuantitativa , Tiofenos/químicaRESUMEN
Chagas disease, caused by the kinetoplastid protozoan parasite Trypanosoma cruzi, remains a relevant cause of illness and premature death and it is estimated that 6 million to 7 million people are infected worldwide. Although chemotherapy options are limited presenting serious problems, such as low efficacy and high toxicity. T. cruzi is susceptible to thiazoles, making this class of compounds appealing for drug development. Previously, thiazoles resulted in an increase in anti-T. cruzi activity in comparison to thiosemicarbazones. Here, we report the structural planning, synthesis and anti-T. cruzi evaluation of new thiazoles derivatives (3a-m and 4a-m), designed from molecular hybridization associated with non-classical bioisosterism. By varying substituents attached to the phenyl and thiazole rings, substituents were observed to retain, enhance or greatly increase their anti-T. cruzi activity, in comparison to the corresponding thiosemicarbazones. In most cases, electron-withdrawing substituents, such as bromine, 3,4-dichloro and nitro groups, greatly increased antiparasitic activity. Specifically, new thiazoles were identified that inhibit the epimastigote proliferation and were toxic for trypomastigotes without affecting macrophages viability. These compounds were also evaluated against cruzain. However, inhibition of this enzyme was not observed, suggesting that the compounds work through another mechanism. In addition, examination of T. cruzi cell death showed that these molecules induce apoptosis. In conclusion, except for compounds 3h and 3k, all thiazoles derivatives evaluated exhibited higher cytotoxic activity against the trypomastigote forms than the reference medicament benznidazole, without affecting macrophages viability. Compounds 4d and 4k were highlights, CC50 = 1.2 e 1.6 µM, respectively. Mechanistically, these compounds do not inhibit the cruzain, but induce T. cruzi cell death by an apoptotic process, being considered a good starting point for the development of new anti-Chagas drug candidates.
Asunto(s)
Apoptosis/efectos de los fármacos , Tiazoles/farmacocinética , Tripanocidas/química , Trypanosoma cruzi/efectos de los fármacos , Enfermedad de Chagas/tratamiento farmacológico , Cisteína Endopeptidasas/efectos de los fármacos , Diseño de Fármacos , Pruebas de Sensibilidad Parasitaria , Proteínas Protozoarias/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/química , Tripanocidas/farmacología , Trypanosoma cruzi/citologíaRESUMEN
We modified the thiazolidinic ring at positions N3, C4, and C5, yielding compounds 6-24. Compounds with a phenyl at position N3, 15-19, 22-24, exhibited better inhibitory properties for cruzain and against the parasite than 2-iminothiazolidin-4-one 5. We were able to identify one high-efficacy trypanocidal compound, 2-minothiazolidin-4-one 18, which inhibited the activity of cruzain and the proliferation of epimastigotes and was cidal for trypomastigotes but was not toxic for splenocytes. Having located some of the structural determinants of the trypanocidal properties, we subsequently wished to determine if the exchange of the thiazolidine for a thiazole ring leaves the functional properties unaffected. We therefore tested thiazoles 26-45 and observed that they did not inhibit cruzain, but they exhibited trypanocidal effects. Parasite development was severely impaired when treated with 18, thus reinforcing the notion that this class of heterocycles can lead to useful cidal agents for Chagas disease.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Iminas/síntesis química , Tiazolidinas/síntesis química , Tripanocidas/síntesis química , Trypanosoma cruzi/efectos de los fármacos , Animales , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Cisteína Endopeptidasas/metabolismo , Femenino , Iminas/química , Iminas/farmacología , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Unión Proteica , Proteínas Protozoarias/antagonistas & inhibidores , Proteínas Protozoarias/metabolismo , Bazo/citología , Estereoisomerismo , Relación Estructura-Actividad , Tiazolidinas/química , Tiazolidinas/farmacología , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma cruzi/metabolismoRESUMEN
We recently showed that oxadiazoles have anti-Trypanosoma cruzi activity at micromolar concentrations. These compounds are easy to synthesize and show a number of clear and interpretable structure-activity relationships (SAR), features that make them attractive to pursue potency enhancement. We present here the structural design, synthesis, and anti-T. cruzi evaluation of new oxadiazoles denoted 5a-h and 6a-h. The design of these compounds was based on a previous model of computational docking of oxadiazoles on the T. cruzi protease cruzain. We tested the ability of these compounds to inhibit catalytic activity of cruzain, but we found no correlation between the enzyme inhibition and the antiparasitic activity of the compounds. However, we found reliable SAR data when we tested these compounds against the whole parasite. While none of these oxadiazoles showed toxicity for mammalian cells, oxadiazoles 6c (fluorine), 6d (chlorine), and 6e (bromine) reduced epimastigote proliferation and were cidal for trypomastigotes of T. cruzi Y strain. Oxadiazoles 6c and 6d have IC(50) of 9.5 ± 2.8 and 3.5 ± 1.8 µM for trypomastigotes, while Benznidazole, which is the currently used drug for Chagas disease treatment, showed an IC(50) of 11.3 ± 2.8 µM. Compounds 6c and 6d impair trypomastigote development and invasion in macrophages, and also induce ultrastructural alterations in trypomastigotes. Finally, compound 6d given orally at 50mg/kg substantially reduces the parasitemia in T. cruzi-infected BALB/c mice. Our drug design resulted in potency enhancement of oxadiazoles as anti-Chagas disease agents, and culminated with the identification of oxadiazole 6d, a trypanosomicidal compound in an animal model of infection.
Asunto(s)
Antiprotozoarios/farmacología , Modelos Animales de Enfermedad , Oxadiazoles/farmacología , Trypanosoma cruzi/efectos de los fármacos , Tripanosomiasis/tratamiento farmacológico , Animales , Antiprotozoarios/administración & dosificación , Antiprotozoarios/química , Relación Dosis-Respuesta a Droga , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Oxadiazoles/administración & dosificación , Oxadiazoles/química , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
New naphthoquinone derivatives were synthesized and assayed against bloodstream trypomastigote forms of Trypanosoma cruzi, the etiological agent of Chagas' disease. The compounds were rationalized based on hybrid drugs and appear as important compounds against this parasite. From nor-lapachol were prepared five substituted ortho-naphthofuranquinones, a non-substituted para-naphthofuranquinone, a new oxyrane and an azide and from alpha-lapachone a new non-substituted para-naphthofuranquinone. Other five substituted ortho-naphthofuranquinones recently designed as cytotoxic, were also evaluated. The most active compounds were the ortho naphthofuranquinones 3-(4-methoxyphenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione and 3-(3-nitrophenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione with trypanocidal activity higher than that of benznidazole, the standard drug. The compounds were rationalized based on hybrid drugs and appear as important compounds against T. cruzi. The trypanocidal activity of these substances endowed with redox properties representing a good starting point for a medicinal chemistry program aiming the chemotherapy of Chagas' disease.
Asunto(s)
Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Naftoquinonas/síntesis química , Naftoquinonas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Antiprotozoarios/química , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular , Naftoquinonas/química , Pruebas de Sensibilidad Parasitaria , EstereoisomerismoRESUMEN
[1,2,3]-Triazole derivatives of nor-beta-lapachone were synthesized and assayed against the infective bloodstream trypomastigote form of Trypanosoma cruzi, the etiological agent of Chagas disease. All the derivatives were more active than the original quinones, with IC(50)/1 day values in the range of 17 to 359 microM, the apolar phenyl substituted triazole 6 being the most active compound. These triazole derivatives of nor-beta-lapachone emerge as interesting new lead compounds in drug development for Chagas disease.
Asunto(s)
Naftoquinonas/química , Triazoles/síntesis química , Triazoles/farmacología , Tripanocidas/síntesis química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Azidas/química , Cationes/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Triazoles/química , Tripanocidas/químicaRESUMEN
Two new diterpenes of the ent-trachylobane type were isolated from the stems of Xylopia langsdorffiana, ent-7alpha-acetoxytrachyloban-18-oic acid (1) and ent-7alpha-hydroxytrachyloban-18-oic acid (2). The structures of these isolates were deduced by spectroscopic data interpretation. X-ray crystallography of 1 was used to confirm its structure. The cytotoxic activity of 1 against V79 fibroblasts and rat hepatocytes was investigated.
Asunto(s)
Annonaceae/química , Diterpenos , Plantas Medicinales/química , Animales , Brasil , Cristalografía por Rayos X , Diterpenos/química , Diterpenos/clasificación , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Fibroblastos/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Masculino , Conformación Molecular , Estructura Molecular , Tallos de la Planta/química , Ratas , Ratas WistarRESUMEN
Four new naphthofuranquinones, obtained from 2-hydroxy-3-allyl-naphthoquinone (1) and nor-lapachol (2), have their structures established by physical and X-ray analysis and their activity evaluated against Trypanosoma cruzi. Compounds 3 and 4 were obtained by addition of iodine to 1 followed by cyclization generating a furan ring. Compound 5 was obtained through the acid-catalyzed reaction by dissolution of 1 in sulfuric acid. Compound 6 was synthesized by addition of bromine and aniline to 2. The IC(50)/24 h for 3-6 in assays with T. cruzi trypomastigotes was between 157 and 640 microM, while the value for crystal violet was 536.0 +/- 3.0 microM. Compounds 3-5 also inhibited epimastigote proliferation. The trypanocidal activity of the new naphthofuranquinones endowed with redox properties reinforces a rational approach in the chemotherapy of Chagas' disease.
Asunto(s)
Naftoquinonas/síntesis química , Naftoquinonas/farmacología , Tripanocidas/síntesis química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Cristalización , Cristalografía por Rayos X , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
The structural characterization of two new, unusual kaurene diterpenes isolated from roots of Erythroxylum barbatum is described. 1D NMR and several 2D shift-correlated NMR pulse sequences (1H,1H-COSY, HMQC, HMBC and NOESY) were used for structure elucidation and the unambiguous 1H and 13C chemical shifts assignments. Single crystal X-ray diffraction analysis was also used to confirm the final relative configuration of the compounds possessing the C-20 methyl and the CH2-15 methylene groups in cis-orientation.