In vitro and Quantitative and Structure Activity Relationship (QSAR) evaluation of the antifungal activity of terpenoid constituents of essential oils against Alternaria alternata and Fusarium oxysporum / Evaluación in vitro y QSAR (Quantitative and Structure-Activity Relationship) de la actividad antifúngica de terpenoides obtenidos de aceites esenciales frente a Alternaria alternata y Fusarium oxysporum

INTRODUCTION: Fungal genera Alternaria and Fusarium include human and plant pathogenic species. Several antifungals have been used for their control, but excessive use has contributed to resistance development in pathogens. An alternative to searching for and developing new antifungal agents is using essential oils and their main components, which have biological activities of interest in medicine and food production. OBJECTIVE: To evaluate in vitro and in silico the antifungal activities of terpenoids against Alternaria alternata and Fusarium oxysporum. MATERIALS AND METHODS: The minimum inhibitory concentration and minimum fungicidal concentration values of 27 constituents of essential oils used against Alternaria alternata and Fusarium oxysporum were evaluated in vitro. In addition, using genetic algorithms, quantitative models of the structure-activity relationship were used to identify the structural and physicochemical properties related to antifungal activity. RESULTS: The evaluated compounds proved to be effective antifungals. Thymol was the most active with a minimum inhibitory concentration of 91.6 ± 28.8 µg/ml for A. alternata and F. oxysporum. Quantitative structure-activity relationship models revealed the octanolwater cleavage ratio as the molecular property, and the phenols as the main functional group contributing to antifungal activity. CONCLUSION: Terpenoids exhibit relevant antifungal activities that should be incorporated into the study of medicinal chemistry. Inclusion of in silico assays in the in vitro evaluation is a valuable tool in the search for and rational design of terpene derivatives as new potential antifungal agents.

Introducción: Los géneros Alternaria y Fusarium contienen especies patógenas para los humanos y los cultivos. Para su control, se han utilizado diversos antifúngicos. Sin embargo, su uso desmedido ha contribuido al desarrollo de agentes patógenos resistentes. Una alternativa para buscar y desarrollar nuevos agentes antimicóticos son los aceites esenciales y sus componentes principales, los cuales poseen diversas actividades biológicas de interés para la medicina y en la preservación de alimentos. Objetivo: Evaluar in vitro e in silico las actividades antifúngicas de terpenoides contra Alternaria alternata y Fusarium oxysporum. Materiales y métodos: Se evaluaron in vitro las concentraciones inhibitorias mínimas y las concentraciones fungicidas mínimas de 27 constituyentes de aceites esenciales contra A. alternata y F. oxysporum. Además, mediante algoritmos genéticos, se crearon modelos cuantitativos de la relación estructura-actividad para determinar las propiedades estructurales y fisicoquímicas relacionadas con la actividad antifúngica. Resultados: Los compuestos evaluados mostraron ser antifúngicos activos. El timol fue el compuesto con mayor actividad, con un valor de concentración inhibitoria mínima de 91.6 ± 28.8 µg/ml, tanto para Alternaria alternata como para Fusarium oxysporum. Los modelos cuantitativos de la relación estructura-actividad incluyeron la avidez por los lípidos y los fenoles como los principales grupos funcionales que contribuyen en la actividad antifúngica. Conclusión: Los terpenoides poseen actividades antifúngicas relevantes para ser incorporados en el estudio de la química medicinal. La inclusión de pruebas in silico a la evaluación in vitro es una herramienta útil para la búsqueda y el diseño racional de derivados terpénicos como posibles agentes antifúngicos.

In vitro and Quantitative and Structure Activity Relationship (QSAR) evaluation of the antifungal activity of terpenoid constituents of essential oils against Alternaria alternata and Fusarium oxysporum / Evaluación in vitro y QSAR (Quantitative and Structure-Activity Relationship) de la actividad antifúngica de terpenoides obtenidos de aceites esenciales frente a Alternaria alternata y Fusarium oxysporum

Introducción. Los géneros Alternaria y Fusarium contienen especies patógenas para los humanos y los cultivos. Para su control, se han utilizado diversos antifúngicos. Sin embargo, su uso desmedido ha contribuido al desarrollo de agentes patógenos resistentes. Una alternativa para buscar y desarrollar nuevos agentes antimicóticos son los aceites esenciales y sus componentes principales, los cuales poseen diversas actividades biológicas de interés para la medicina y en la preservación de alimentos. Objetivo. Evaluar in vitro e in silico las actividades antifúngicas de terpenoides contra Alternaria alternata y Fusarium oxysporum. Materiales y métodos. Se evaluaron in vitro las concentraciones inhibitorias mínimas y las concentraciones fungicidas mínimas de 27 constituyentes de aceites esenciales contra A. alternata y F. oxysporum. Además, mediante algoritmos genéticos, se crearon modelos cuantitativos de la relación estructura-actividad para determinar las propiedades estructurales y fisicoquímicas relacionadas con la actividad antifúngica. Resultados. Los compuestos evaluados mostraron ser antifúngicos activos. El timol fue el compuesto con mayor actividad, con un valor de concentración inhibitoria mínima de 91.6 ± 28.8 pg/ml, tanto para Alternarla alternata como para Fusarium oxysporum. Los modelos cuantitativos de la relación estructura-actividad incluyeron la avidez por los lípidos y los fenoles como los principales grupos funcionales que contribuyen en la actividad antifúngica. Conclusión. Los terpenoides poseen actividades antifúngicas relevantes para ser incorporados en el estudio de la química medicinal. La inclusión de pruebas in silico a la evaluación in vitro es una herramienta útil para la búsqueda y el diseño racional de derivados terpénicos como posibles agentes antifúngicos.

Introduction. Fungal genera Alternaría and Fusarium include human and plant pathogenic species. Several antifungals have been used for their control, hut excessive use has contributed to resistance development in pathogens. An alternative to searching for and developing new antifungal agents is using essential oils and their main components, which have biological activities of interest in medicine and food production. Objective. To evaluate in vitro and in silico the antifungal activities of terpenoids against Alternaria alternata and Fusarium oxysporum. Materials and methods. The minimum inhibitory concentration and minimum fungicidal concentration values of 27 constituents of essential oils used against Alternaria alternata and Fusarium oxysporum were evaluated in vitro. In addition, using genetic algorithms, quantitative models of the structure-activity relationship were used to identify the structural and physicochemical properties related to antifungal activity. Results. The evaluated compounds proved to be effective antifungals. Thymol was the most active with a minimum inhibitory concentration of 91.6 ± 28.8 pg/ml for A. alternata and F. oxysporum. Quantitative structure-activity relationship models revealed the octanol-water cleavage ratio as the molecular property, and the phenols as the main functional group contributing to antifungal activity. Conclusion. Terpenoids exhibit relevant antifungal activities that should be incorporated into the study of medicinal chemistry. Inclusion of in silico assays in the in vitro evaluation is a valuable tool in the search for and rational design of terpene derivatives as new potential antifungal agents.

Structure-activity relationships study of mTOR kinase inhibition using QSAR and structure-based drug design approaches.

The discovery of clinically relevant inhibitors of mammalian target of rapamycin (mTOR) for anticancer therapy has proved to be a challenging task. The quantitative structure-activity relationship (QSAR) approach is a very useful and widespread technique for ligand-based drug design, which can be used to identify novel and potent mTOR inhibitors. In this study, we performed two-dimensional QSAR tests, and molecular docking validation tests of a series of mTOR ATP-competitive inhibitors to elucidate their structural properties associated with their activity. The QSAR tests were performed using partial least square method with a correlation coefficient of r2=0.799 and a cross-validation of q2=0.714. The chemical library screening was done by associating ligand-based to structure-based approach using the three-dimensional structure of mTOR developed by homology modeling. We were able to select 22 compounds from two databases as inhibitors of the mTOR kinase active site. We believe that the method and applications highlighted in this study will help future efforts toward the design of selective ATP-competitive inhibitors.