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El compromiso con las ojivas electrófilas y la relación estructura-actividad de los inhibidores covalentes putativos

Sofia Kanwal¹, Anees Saeed¹, Ayesha Tahir¹

¹Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, 22060 Abbottabad, Pakistan.

Bioorganic chemistry

|February 21, 2026

Resumen

Los nuevos derivados del benzothiazol muestran un fuerte potencial como inhibidores de la proteasa principal (M^pro) del SARS-CoV-2. El compuesto 35 demuestra una alta potencia y selectividad, con una seguridad favorable y estabilidad estructural.

Área de la Ciencia:

Química Medicinal La Química Medicinal es un campo de estudio de la química medicinal.
Descubrimiento de Drogas Descubrimiento de Drogas
Virología Virología.

Sus antecedentes:

El síndrome respiratorio agudo severo coronavirus 2 (SARS-CoV-2) causa una crisis de salud global.
La proteasa principal del SARS-CoV-2 (M^pro) es una enzima viral crucial y un objetivo de fármaco validado.
Los tratamientos existentes se enfrentan a desafíos, lo que requiere nuevas estrategias terapéuticas.

Objetivo del estudio:

Diseñar, sintetizar y evaluar nuevos derivados del benzothiazol como inhibidores M^pro del SARS-CoV-2.
Para optimizar los compuestos de plomo para una mayor potencia, selectividad y seguridad.
Para aclarar el mecanismo de unión y la dinámica estructural de los inhibidores potentes.

Principales métodos:

Síntesis de productos intermedios y derivados basados en el benzothiazol.
Ensayos enzimáticos in vitro para determinar la inhibición de M^pro (IC₅₀).
Ensayos de citotoxicidad (CC₅₀) y estudios de toxicidad oral aguda (LD₅₀).
Acoplamiento molecular y simulaciones de dinámica molecular (DM).
Análisis histopatológico de tejidos hepáticos.

Principales resultados:

Los intermediarios iniciales mostraron una inhibición moderada de M^pro y una citotoxicidad de baja a moderada.
La optimización del plomo produjo el compuesto 35 con IC nanomolar ₅₀ (0.026 μM) y un alto índice de selectividad (10.653,8).
El compuesto 35 exhibió una baja toxicidad oral aguda (LD₅₀ = 947.6 mg/kg) y conservó la arquitectura hepática.
El modelado molecular confirmó la unión potente dentro del sitio activo M^pro, incluida una interacción covalente putativa para el compuesto 35.
Las simulaciones de MD indicaron que el compuesto 35 estabiliza la estructura M^pro.

Conclusiones:

Los andamios de benzotiazol son prometedores para el desarrollo de inhibidores efectivos del SARS-CoV-2 M^pro.
El Compuesto 35 representa un inhibidor M^pro altamente potente y selectivo con un perfil de seguridad favorable.
Un mayor desarrollo de estos compuestos podría conducir a nuevas terapias antivirales contra el SARS-CoV-2.

Palabras clave:

El benzotiazol es el benzotiazol.El acoplamiento de acoplamiento covalente.La proteasa principal es la proteasa.Los supuestos inhibidores covalentes putativos.El SARS-CoV-2 es el

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