RESUMEN
The complications of Alzheimer's disease AD were deadly dangerous cause of neurodegenerative disorders connected with the decline of the cognitive functions and loss of memory. The common form of dementia is accounted as the sixth leading cause of the death affecting any stage of people in a lifetime. Synthetic natural chalcone analogs were currently a hot research topic for the treatment of (AD) which has affected millions of peoples throughout the world. The present aim was set to understand the important problems of the AD and its treatment based on natural derivatives of novel chalcones. One interesting strategy currently of searching for the treatment of AD is to find inhibitors for acetylcholinesterase (AChE) and using metal chelators to target amyloid-ß (Aß) peptides, and then metal-Aß complexes for the AD pathogenesis. The present compressed review focuses and highlights the design and synthesis of new approaches for the construction of important chalcones playing multiple beneficiary roles in the AD treatments. These hallmarks of concurred research represent the immediate needs of development of novel therapeutic drugs for effective treatment of ADs by understanding the specific pharmacology targets.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Chalconas/uso terapéutico , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Chalconas/química , Chalconas/metabolismo , Quelantes/química , Quelantes/uso terapéutico , Diseño de Fármacos , Humanos , Simulación del Acoplamiento Molecular , Monoaminooxidasa/química , Monoaminooxidasa/metabolismoRESUMEN
A series of chalcone derivatives were designed, synthesized, and evaluated for their cytotoxic potential. These molecules have showed promising cytotoxic activity with IC50 values ranging from 5.24 to 63.12 µm. Among them, conjugates 16k, 16m and 16t showed significant antiproliferative activity with IC50 values ranging from 5.24 to 10.39 µm in MDA-MB-231 cell line. These compounds were further investigated for their effect on cell membrane blebbing, chromatin condensation, DNA fragmentation, Hoechst staining, annexin V, and cell cycle arrest (G2/M). The Western blot experiments revealed up regulation of pro-apoptotic Bax and downregulation of antiapoptotic Bcl-2. The studies also indicated reduction of mitochondrial membrane potential and increase in the levels of caspase-3 and caspase-7.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Chalconas/química , Chalconas/farmacología , Antineoplásicos/síntesis química , Mama/efectos de los fármacos , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Chalconas/síntesis química , Femenino , HumanosRESUMEN
2-Styryl quinolines (9a-l) have been synthesized regioselectively from 2-methyl-quinoline by using NaOAc in water acetic acid binary solvents and evaluated for their antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the compounds 12 and 8 were found to be active against both bacterial strains. Compounds 9b, 9f, 9g, 9i, 9j and 9k were the most active among the series exhibiting MIC values ranging between 1.9 and 31.2 µg ml(-1) against different bacterial strains. Compounds 9j and 9k were found to be as potent as the standard drug ciprofloxacin against Micrococcus luteus, Klebsiella planticola and Staphylococcus aureus. In addition, the compounds showed bactericidal activity; compound 9j was found to be better than ciprofloxacin, with an MBC value of 0.9 µg ml(-1) against both M. luteus and K. planticola. The compounds also inhibited biofilm formation, and compound 9j was found to be equipotent to erythromycin against M. luteus and S. aureus MLS16. Further, theoretical studies such as those on druggable properties and PMI plot have been carried out.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Simulación por Computador , Quinolinas/síntesis química , Quinolinas/farmacología , Antibacterianos/química , Bacterias/efectos de los fármacos , Biopelículas/efectos de los fármacos , Técnicas de Química Sintética , Aprobación de Drogas , Pruebas de Sensibilidad Microbiana , Quinolinas/química , Estereoisomerismo , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
A series of chalcone conjugates featuring the imidazo[2,1-b]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF-7, A549, HeLa, DU-145 and HT-29). These new hybrid molecules have shown promising cytotoxic activity with IC50 values ranging from 0.64 to 30.9 µM. Among them, (E)-3-(6-(4-fluorophenyl)-2,3-bis(4-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)-1-(pyridin-2-yl)prop-2-en-1-one (11 x) showed potent antiproliferative activity with IC50 values ranging from 0.64 to 1.44 µM in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate (11 x) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell-cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase-3, DNA fragmentation analysis, and Annexin V-FITC assay. Moreover, molecular docking studies indicated that this conjugate (11 x) interacts and binds efficiently with the tubulin protein.