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1.
Chem Biol Drug Des ; 101(6): 1283-1298, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36762979

RESUMEN

A series of novel noncovalent glycine/ß-alanine anilide derivatives possessing 2-chloronaphthoquinone structure as a pharmacophoric unit were designed, synthesized, and evaluated for their antiproliferative and antiproteasomal activities against MCF-7 cell line, in vitro. According to biological activity results, all the target compounds showed antiproliferative activity in the range of IC50  = 7.10 ± 0.10-41.08 ± 0.14 µM and most of them exhibited inhibitory efficacy with varying ratios against the three catalytic subunits (ß1, ß2, and ß5) presenting caspase-like (C-L), trypsin-like (T-L) and chymotrypsin-like (ChT-L) activities of proteasome. The antiproteasomal activity evaluations revealed that compounds preferentially inhibited the ß5 subunit compared with ß1 and ß2 subunits of the proteasome. Among the compounds, compounds 7 and 9 showed the highest antiproliferative activity with an IC50 value of 7.10 ± 0.10 and 7.43 ± 0.25 µM, respectively. Additionally, compound 7 displayed comparable potency to PI-083 lead compound in terms of ß5 antiproteasomal activity with an inhibition percentage of 34.67 at 10 µM. This compound showed an IC50 value of 32.30 ± 0.45 µM against ß5 subunit. Furthermore, molecular modeling studies of the most active compound 7 revealed key interactions with ß5 subunit. The results suggest that this class of compounds may be beneficial for the development of new potent proteasome inhibitors.


Asunto(s)
Antineoplásicos , Naftoquinonas , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/química , Complejo de la Endopetidasa Proteasomal , Glicina/farmacología , Naftoquinonas/farmacología , Naftoquinonas/química , beta-Alanina/farmacología , Anilidas/farmacología , Relación Estructura-Actividad , Estructura Molecular , Proliferación Celular , Antineoplásicos/farmacología
2.
Eur J Med Chem ; 209: 112890, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33039723

RESUMEN

A series of novel 4-aminobenzensulfonamide/carboxamide derivatives bearing naphthoquinone pharmacophore were designed, sythesized and evaluated for their proteasome inhibitory and antiproliferative activities against human breast cancer cell line (MCF-7). The structures of the synthesized compounds were confirmed by spectral and elemental analyses. The proteasome inhibitory activity studies were carried out using cell-based assay. The antiproteasomal activity results revealed that most of the compounds exhibited inhibitory activity with different percentages against the caspase-like (C-L, ß1 subunit), trypsin-like (T-L, ß2 subunit) and chymotrypsin-like (ChT-L, ß5 subunit) activities of proteasome. Among the tested compounds, compound 14 bearing 5-chloro-2-pyridyl ring on the nitrogen atom of sulfonamide group is the most active compound in the series and displayed higher inhibition with IC50 values of 9.90 ± 0.61, 44.83 ± 4.23 and 22.27 ± 0.15 µM against ChT-L, C-L and T-L activities of proteasome compared to the lead compound PI-083 (IC50 = 12.47 ± 0.21, 53.12 ± 2.56 and 26.37 ± 0.5 µM), respectively. The antiproliferative activity was also determined by MTT (3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay in vitro. According to the antiproliferative activity results, all of the compounds exhibited cell growth inhibitory activity in a range of IC50 = 1.72 ± 0.14-20.8 ± 0.5 µM and compounds 13 and 28 were found to be the most active compounds with IC50 values of 1.79 ± 0.21 and 1.72 ± 0.14 µM, respectively. Furthermore, molecular modeling studies were carried out for the compounds 13, 14 and 28 to investigate the ligand-enzyme binding interactions.


Asunto(s)
Naftoquinonas/química , Naftoquinonas/farmacología , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Derivados del Benceno/síntesis química , Derivados del Benceno/química , Derivados del Benceno/farmacología , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Naftoquinonas/síntesis química , Inhibidores de Proteasoma/síntesis química , Sulfonamidas/síntesis química
3.
Arch Pharm (Weinheim) ; 351(3-4): e1700273, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29527733

RESUMEN

A series of N-substituted-5-chloro-2(3H)-benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory, and antioxidant activities. The structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The free radical scavenging activity was also determined by in vitro ABTS (2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)) assay. The biological activity results revealed that all of the title compounds displayed higher AChE inhibitory activity than the reference compound, rivastigmine, and were selective for AChE. Among the tested compounds, compound 7 exhibited the highest inhibition against AChE (IC50 = 7.53 ± 0.17 µM), while compound 11 was found to be the most active compound against BuChE (IC50 = 17.50 ± 0.29 µM). The molecular docking study of compound 7 showed that this compound can interact with the catalytic active site (CAS) of AChE and also has potential metal chelating ability and a proper log P value. On the other hand, compound 2 bearing a methyl substituent at the ortho position on the phenyl ring showed better radical scavenging activity (IC50 = 1.04 ± 0.04 mM) than Trolox (IC50 = 1.50 ± 0.05 mM).


Asunto(s)
Benzoxazoles/farmacología , Inhibidores de la Colinesterasa/farmacología , Simulación del Acoplamiento Molecular , Acetilcolinesterasa/metabolismo , Animales , Benzoxazoles/síntesis química , Benzoxazoles/química , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Electrophorus , Caballos , Bases de Mannich/síntesis química , Bases de Mannich/química , Bases de Mannich/farmacología , Estructura Molecular , Relación Estructura-Actividad
4.
J Enzyme Inhib Med Chem ; 32(1): 13-19, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27766908

RESUMEN

A series of 4-phthalimidobenzenesulfonamide derivatives were designed, synthesized and evaluated for the inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The biological activity results revealed that all of the title compounds (except for compound 8) displayed high selectivity against AChE. Among the tested compounds, compound 7 was found to be the most potent against AChE (IC50= 1.35 ± 0.08 µM), while compound 3 exhibited the highest inhibition against BuChE (IC50= 13.41 ± 0.62 µM). Molecular docking studies of the most active compound 7 in AChE showed that this compound can interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.


Asunto(s)
Acetilcolinesterasa/efectos de los fármacos , Butirilcolinesterasa/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Simulación del Acoplamiento Molecular , Ftalimidas/química , Sulfonamidas/farmacología , Análisis Espectral/métodos , Sulfonamidas/química , Bencenosulfonamidas
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