ABSTRACT
New series of thiophene-containing phenoxypropanolamines were synthesized and evaluated for their potency to inhibit the three proteolytic activities of the mammalian 20S proteasome. Noticeable inhibition of both ChT-L and PA activities was obtained with three compounds: one with unsubstituted phenoxypropanolamine group (7) and the two others with a p-Cl-substituted group (4 and 9). For three other compounds (3, 8 and 10), ChT-L activity alone was significantly inhibited. In silico docking performed on the ß5 and ß1 subunits bearing the respective ChT-L and PA catalytic sites showed features common to poses associated with active compounds. These features may constitute a selectivity criterion for structure-guided inhibitor design.
Subject(s)
Phenoxypropanolamines/chemistry , Proteasome Endopeptidase Complex/chemistry , Proteasome Inhibitors/chemistry , Animals , Binding Sites , Catalytic Domain , Cattle , Inhibitory Concentration 50 , Molecular Docking Simulation , Mycobacterium tuberculosis/enzymology , Phenoxypropanolamines/chemical synthesis , Phenoxypropanolamines/metabolism , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/chemical synthesis , Proteasome Inhibitors/metabolism , Protein Subunits/antagonists & inhibitors , Protein Subunits/metabolism , Structure-Activity RelationshipABSTRACT
A biocatalytic route for the synthesis of a potential ß-blocker, (S)-moprolol is reported here. Enantiopure synthesis of moprolol is mainly dependent on the chiral intermediate, 3-(2-methoxyphenoxy)-propane-1,2-diol. Various commercial lipases were screened for the enantioselective resolution of (RS)-3-(2-methoxyphenoxy)propane-1,2-diol to produce the desired enantiomer. Among them, Aspergillus niger lipase (ANL) was selected on the basis of both stereo- and regioselectivity. The optimized values of various reaction parameters were determined such as enzyme (15 mg/mL), substrate concentration (10 mM), organic solvent (toluene), reaction temperature (30 °C), and time (18 h).The optimized conditions led to achieving >49% yield with high enantiomeric excess of (S)-3-(2-methoxyphenoxy)propane-1,2-diol. The lipase-mediated catalysis showed regioselective acylation with dual stereoselectivity. Further, the enantiopure intermediate was used for the synthesis of (S)-moprolol, which afforded the desired ß-blocker.
Subject(s)
Adrenergic beta-Antagonists/chemistry , Lipase/chemistry , Phenoxypropanolamines/chemical synthesis , Acylation , Adrenergic beta-Antagonists/metabolism , Biocatalysis , Catalysis , Lipase/metabolism , Propanols/chemistry , StereoisomerismABSTRACT
Five active pharmaceutical ingredients (APIs) containing the vicinyl amino alcohol moiety were synthesized using a convergent chemical assembly system. The continuous system is composed of four flow reaction modules: biphasic oxidation, Corey-Chaykovsky epoxidation, phenol alkylation, and epoxide aminolysis. Judicious choice of reagents and module order allowed for two classes of ß-amino alcohols, aryl and aryloxy, to be synthesized in good (27-69%) overall yields.
Subject(s)
Phenoxypropanolamines/chemical synthesis , Anti-Arrhythmia Agents/chemical synthesis , Antihypertensive Agents/chemical synthesis , Bronchodilator Agents/chemical synthesis , Chemistry Techniques, Synthetic , Epichlorohydrin/chemistry , Epoxy Compounds/chemical synthesis , StereoisomerismABSTRACT
In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, we prepared a novel series of phenoxypropanolamine derivatives containing the thiourea moiety and evaluated their biological activities at human beta3-, beta2-, and beta1-ARs. Among these compounds, 4-nitrophenylthiourea (18i) and 3-methoxyphenylthiourea (18k) derivatives were found to exhibit potent agonistic activity at the beta3-AR, with EC(50) values of 0.10 and 0.16 microM, respectively, and no agonistic activity for either the beta1- or beta2-AR. In addition, they showed significant hypoglycemic activity in a rodent diabetic model.
Subject(s)
Adrenergic Agonists/chemistry , Adrenergic Agonists/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Phenoxypropanolamines/chemistry , Phenoxypropanolamines/therapeutic use , Receptors, Adrenergic, beta/metabolism , Adrenergic Agonists/chemical synthesis , Adrenergic Agonists/pharmacology , Adrenergic beta-3 Receptor Antagonists , Animals , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Mice , Molecular Structure , Obesity/drug therapy , Phenoxypropanolamines/chemical synthesis , Phenoxypropanolamines/pharmacology , Receptors, Adrenergic, beta-3/metabolism , Structure-Activity Relationship , Thiourea/chemical synthesis , Thiourea/chemistry , Thiourea/pharmacology , Thiourea/therapeutic useABSTRACT
In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the beta3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective beta3-AR agonist, with an EC(50) value of 0.28 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model.
