RESUMEN
An efficient solution-phase parallel synthesis of alkylated guanidines from commercial thioisocyanates and amines is described. In the first step, a thioisocyanate reacts with one equivalent of ammonia or a primary or secondary amine to give a thiourea intermediate. The latter is S-alkylated with n-dodecyl bromide resulting in the corresponding thiouronium bromide. Finally, the reaction of the thiouronium salt with a second equivalent of ammonia or a primary amine yields an alkylated guanidine. All three synthetic steps are easily combined in a one-pot high-yielding procedure with a simple work-up. Ca. 250 guanidine derivatives with high structural and functional diversity were synthesized by the developed method. 35 representatives reported in this study were fully characterized.
Asunto(s)
Aminas/metabolismo , Guanidinas/síntesis química , Isocianatos/metabolismo , Aminas/química , Catálisis , Guanidinas/química , Guanidinas/metabolismo , Isocianatos/química , Estructura MolecularRESUMEN
The parallel solution-phase synthesis of substituted thieno[2,3- d]pyrimidin-6-carboxylic acids has been accomplished. This strategy relies on a cyclization of 2-aminothiophen-3,5-dicarboxylates with a set of nitriles, followed by hydrolysis to construct the library of corresponding acids. The convenient procedure for use and dosage of dry HCl for the reaction was elaborated and adapted for semiautomated solution-phase parallel synthesis. With the use of another (hetero)aromatic ortho-aminocarboxylate, mini-libraries of diverse fused pyrimidin-4-ones were synthesized. The scope and limitations of the approach are discussed.
Asunto(s)
Ácido Clorhídrico/química , Pirimidinonas/síntesis química , Técnicas Químicas Combinatorias , Ciclización , Ácidos Dicarboxílicos/química , Nitrilos/química , Bibliotecas de Moléculas Pequeñas/síntesis química , SolucionesRESUMEN
An approach to the parallel synthesis of hydantoin libraries by reaction of in situ generated 2,2,2-trifluoroethylcarbamates and α-amino esters was developed. To demonstrate utility of the method, a library of 1158 hydantoins designed according to the lead-likeness criteria (MW 200-350, cLogP 1-3) was prepared. The success rate of the method was analyzed as a function of physicochemical parameters of the products, and it was found that the method can be considered as a tool for lead-oriented synthesis. A hydantoin-bearing submicromolar primary hit acting as an Aurora kinase A inhibitor was discovered with a combination of rational design, parallel synthesis using the procedures developed, in silico and in vitro screenings.
Asunto(s)
Aurora Quinasa A/antagonistas & inhibidores , Hidantoínas/síntesis química , Aurora Quinasa A/química , Sitios de Unión , Técnicas Químicas Combinatorias , Simulación por Computador , Hidantoínas/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Bibliotecas de Moléculas Pequeñas , Relación Estructura-ActividadRESUMEN
Multigram synthesis of (chlorosulfonyl)benzenesulfonyl fluorides is described. Selective modification of these building blocks at the sulfonyl chloride function under parallel synthesis conditions is achieved. It is shown that the reaction scope includes the use of (hetero)aromatic and electron-poor aliphatic amines (e.g., amino nitriles). Utility of the method is demonstrated by preparation of the sulfonyl fluoride library for potential use as covalent fragments, which is demonstrated by a combination of in silico and in vitro screening against trypsin as a model enzyme. As a result, several inhibitors were identified with activity on par with that of the known inhibitor.
Asunto(s)
Inhibidores de Serina Proteinasa/síntesis química , Bibliotecas de Moléculas Pequeñas/síntesis química , Sulfonas/síntesis química , Catálisis , Técnicas Químicas Combinatorias , Simulación por Computador , Simulación del Acoplamiento Molecular , Paladio/química , Unión Proteica , Conformación Proteica , Sulfonamidas/químicaRESUMEN
One-pot synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from carboxylic acids and nitriles was optimized to parallel chemistry. The method was validated on a 141 member library; the desired products were recovered with a high success rate and in moderate yields. Practical application of the approach was demonstrated in the synthesis of bioactive compound pifexole and agonists of free fatty acid receptor 1. A library of 4â¯948â¯100 synthesizable drug-like 3,5-disubstituted 1,2,4-oxadiazoles was enumerated based on the method and available validated reagents.
Asunto(s)
Ácidos Carboxílicos/química , Nitrilos/química , Oxadiazoles/química , Humanos , Oximas/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Relación Estructura-ActividadRESUMEN
A simple and cost-effective one-pot parallel synthesis approach to sulfides, sulfoxides, and sulfones from thiourea was elaborated. The method combines two procedures optimized to the parallel synthesis conditions: alkylation of thiourea with alkyl chlorides and mono or full oxidation of in situ generated sulfides with H2O2 or H2O2-(NH4)2MoO4. The experimental set up required commonly used lab equipment: conventional oven and ultrasonic bath; the work up includes filtration or extraction with chloroform. The method was evaluated on an 81 member library of drug-like sulfides, sulfoxides, and sulfones yielding the compounds on a 30-300 mg scale. A small-scale synthesis of 2-(benzhydrylsulfinyl)acetamide (modafinil) utilizing our approach resulted in similar efficiency to the published procedures.
Asunto(s)
Sulfuros/síntesis química , Sulfonas/síntesis química , Sulfóxidos/síntesis química , Alquilación , Compuestos de Bencidrilo/síntesis química , Cloroformo , Filtración , Indicadores y Reactivos , Modafinilo , Molibdeno/química , Oxidación-Reducción , Solventes , Tiourea/química , UltrasonidoRESUMEN
A one-pot parallel synthesis of N(1)-aryl-N(2)-alkyl-substituted oxamides with 2,2,2-trifluoroethyl chlorooxoacetate was developed. The synthesis of a library of 45 oxamides revealed higher efficiency of this reagent over the known ethyl chlorooxoacetate. The reagent was successfully used to prepare the known oxamide-containing HIV entry inhibitors.
Asunto(s)
Amidas/química , Glioxilatos/química , Oxalatos/química , Amidas/síntesis química , Aminas/síntesis química , Aminas/química , Inhibidores de Fusión de VIH/síntesis química , Indicadores y Reactivos , Bibliotecas de Moléculas PequeñasRESUMEN
Two types of aliphatic sulfonyl halides (Cl versus F) were compared in parallel synthesis of sulfonamides derived from aliphatic amines. Aliphatic sulfonyl fluorides showed good results with amines bearing an additional functionality, while the corresponding chlorides failed. Both sulfonyl halides were effective in the reactions with amines having an easily accessible amino group. Aliphatic sulfonyl chlorides reacted efficiently with amines bearing sterically hindered amino group while the corresponding fluorides showed low activity.
Asunto(s)
Ácidos Sulfínicos/química , Sulfonamidas/síntesis química , Estructura Molecular , Sulfonamidas/químicaRESUMEN
One-pot parallel synthesis of unsymmetrical aliphatic ureas was achieved with bis(2,2,2-trifluoroethyl) carbonate. The procedure worked well for both the monosubstituted and functionalized alkyl amines and required no special conditions (temperature control, order, or rate of addition). A library of 96 diverse ureas was easily synthesized.
Asunto(s)
Ésteres/química , Urea/análogos & derivados , Urea/síntesis química , Estructura Molecular , Urea/químicaRESUMEN
A parallel reductive amination of heteroaromatic amines has been performed using a combination of ZnCl2-TMSOAc (activating agents) and NaBH(OAc)3 (reducing agent). A library of diverse secondary amines was easily prepared on a 50-300 mg scale.
Asunto(s)
Aldehídos/química , Aminas/síntesis química , Hidrocarburos Aromáticos/síntesis química , Bibliotecas de Moléculas Pequeñas/síntesis química , Aldehídos/síntesis química , Aminación , Aminas/química , Cloruros/química , Técnicas Químicas Combinatorias , Hidrocarburos Aromáticos/química , Oxidación-Reducción , Sustancias Reductoras/química , Bibliotecas de Moléculas Pequeñas/química , Compuestos de Zinc/químicaRESUMEN
The parallel solution-phase synthesis of more than 230 substituted thieno[2,3-d]pyrimidin-2-ylmethanamines has been accomplished. This strategy is based on the cyclization of 2-aminothiophen-3-carboxylates with chloroacetonitrile to construct the thieno[2,3-d]pyrimidine core with two diversity points. Derivatization of the active chlorine and functionalization of C-4 position of the pyrimidine ring allow the introduction of other diversity points. The products containing ester groups at the 6-position of the thieno[2,3-d]pyrimidine were used in amide synthesis. Simple manual techniques for parallel reactions, coupled with simple purification procedures, gave highly pure final products. The scope and limitations of the approach are discussed.