RESUMEN
Background: Possible bioisosteres can be developed by replacing the 1-indanone ring (one of three pharmacophore groups) of donepezil with an indoline ring. As H2S donors, thioamide, thiocarbamate and thiourea groups are also critically important. Materials & methods: The 1-benzyl-2-indolinones 6a-n were designed using molecular modeling and synthesized, and their acetylcholinesterase and butyrylcholinesterase inhibitory effects were then investigated. Results: The compounds 6h (inhibition constant [Ki] = 0.22 µM; selectivity index [SI] = 26.22), 6i (Ki = 0.24 µM; SI = 25.83), 6k (Ki = 0.22 µM; SI = 28.31) and 6n (Ki = 0.21 µM; SI = 27.14) were approximately twofold more effective against and >12-fold more selective for acetylcholinesterase compared with donepezil (Ki = 0.41 µM; SI = 2.12). Analysis of molecular dynamics simulations with compounds 6k and 6n indicated that the preferred binding might be at allosteric binding pocket 4 of the enzyme. Conclusion: Benzyl substitution at the 1-position of the indole ring significantly increased potency and selectivity.
Asunto(s)
Acetilcolinesterasa , Butirilcolinesterasa , Acetilcolinesterasa/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Donepezilo , Oxindoles , Relación Estructura-Actividad , Simulación del Acoplamiento MolecularRESUMEN
1-Methyl/ethyl/benzyl-5-(un)substituted 1H-indole-2,3-diones (2, 3, and 4) were synthesized by reaction of 5-(un)substituted 1H-indole-2,3-diones (1) with methyl iodide, ethyl chloride, and benzyl bromide. (3-Sulfamoylphenyl)isothiocyanate (6) was obtained by the treatment of 3-aminobenzenesulfonamide (5) with thiophosgene. Compound 6 was reacted with hydrazine to yield 4-(3-sulfamoylphenyl)thiosemicarbazide (7). Novel 1-(un)substituted/methyl/ethyl/benzyl-5-(un)substituted 1H-indole-2,3-dione 3-[4-(3-sulfamoylphenyl)thiosemicarbazone] derivatives (8-11) were prepared by condensation of 7 and 1-4. The structures of the synthesized compounds were confirmed by elemental analysis and spectral data. Inhibition of the widely distributed cytosolic off-targets human carbonic anhydrases (hCAs) I and II, and two tumor-associated membrane-bound isoforms (hCAs IX and XII), by 8-11 was investigated. The hCA II inhibitory effects of all tested compounds were in the subnanomolar to low nanomolar levels (Ki = 0.32-83.3 nM), and generally high selectivity for hCA II isoenzyme over hCA I, IX, and XII isoenzymes was observed. The strongest inhibitors of hCA II, 1-benzyl-5-(trifluoromethoxy)-substituted 11c (Ki = 0.32 nM) and 1-ethyl-5-chloro-substituted 10e (Ki = 0.35 nM), were docked within the enzyme active site. Molecular modeling studies with the most effective hCA IX and XII inhibitors were also carried out.
Asunto(s)
Anhidrasas Carbónicas , Tiosemicarbazonas , Anhidrasa Carbónica I , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Humanos , Indoles/farmacología , Isoenzimas , Estructura Molecular , Relación Estructura-Actividad , Tiosemicarbazonas/farmacologíaRESUMEN
Inhibition of the ß-carbonic anhydrase (CA, EC 4.2.1.1) from pathogenic Candida glabrata (CgNce103) by 1H-indole-2,3-dione 3-[N-(4-sulfamoylphenyl)thiosemicarbazones] 4a-m was investigated. All the compounds were found to be potent inhibitors of CgNce103, with inhibition constants in the range of 6.4-63.9 nM. The 5,7-dichloro substituted derivative 4l showed the most effective inhibition (KI of 6.4 nM) as well as the highest selectivity for inhibiting CgNce103 over the cytosolic human (h) isoforms hCA I and II. A possible binding interaction of compound 4l within the active site of CgNce103 has been proposed based on docking studies.
Asunto(s)
Candida albicans/enzimología , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Oxindoles/farmacología , Sulfonamidas/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxindoles/síntesis química , Oxindoles/química , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
Human carbonic anhydrases IX and XII are upregulated in many tumors and form a novel target for new generation anticancer drugs. Here we report the synthesis of novel 2-indolinone derivatives with the sulfonamide group as a zinc binding moiety. Enzyme inhibition assays confirmed that the compounds showed selectivity against hCA IX and XII over the widely distributed off-targets hCA I and II. Molecular modelling studies were performed to suggest modes of binding for these compounds.