RESUMO
This work describes the synthesis of 3-hydroxy-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,8-diones, their tautomerism, and reactivity towards binucleophiles. These molecules are novel and convenient building-blocks for the direct construction of biologically important polycyclic pyridones via an oxazinone ring-opening transformation promoted with ammonium acetate or acetic acid. In the case of o-phenylenediamine, partial aromatization of the obtained heterocycles proceeded to form polycyclic benzimidazole-fused pyridones (33-91%).
RESUMO
Glucopyranosylidene-spiro-benzo[ b][1,4]oxazinones were obtained via the corresponding 2-nitrophenyl glycosides obtained by two methods: (a) AgOTf-promoted glycosylation of 2-nitrophenol derivatives by O-perbenzoylated methyl (α-d-gluculopyranosyl bromide)heptonate or (b) Mitsunobu-type reactions of O-perbenzoylated methyl (α-d-gluculopyranose)heptonate with bulky 2-nitrophenols in the presence of diethyl azodicarboxylate (DEAD) and PPh3. Catalytic hydrogenation (H2-Pd/C) or partial reduction (e.g., H2-Pd/C, pyridine) of the 2-nitro groups led to spiro-benzo[ b][1,4]oxazinones and spiro-benzo[ b][1,4]-4-hydroxyoxazinones by spontaneous ring closure of the intermediate 2-aminophenyl or 2-hydroxylamino glycosides, respectively. The analogous 2-aminophenyl thioglycosides, prepared by reactions of O-perbenzoylated methyl (α-d-gluculopyranosyl bromide)heptonate with 2-aminothiophenols, were cyclized in m-xylene at reflux temperature to the corresponding spiro-benzo[ b][1,4]thiazinones. O-Debenzoylation was effected by Zemplén transesterification in both series. Spiro-configurations were determined by NMR and electronic circular dichroism time-dependent density functional theory (ECD-TDDFT) methods. Inhibition assays with rabbit muscle glycogen phosphorylase b showed (1' R)-spiro{1',5'-anhydro-d-glucitol-1',2-benzo[ b][1,4]oxazin-3(4 H)-one} and (1' R)-spiro{1',5'-anhydro-d-glucitol-1',2-benzo[ b][1,4]thiazin-3(4 H)-one} to be the most efficient inhibitors (27 and 28% inhibition at 625 µM, respectively). Plant growth tests with white mustard and garden cress indicated no effect except for (1' R)-4-hydroxyspiro{1',5'-anhydro-d-glucitol-1',2-benzo[ b][1,4]oxazin-3(4 H)-one} with the latter plant to show modest inhibition of germination (95% relative to control).
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glicogênio Fosforilase/antagonistas & inibidores , Lepidium sativum/efeitos dos fármacos , Mostardeira/efeitos dos fármacos , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Animais , Inibidores Enzimáticos/química , Esterificação , Germinação/efeitos dos fármacos , Glicogênio Fosforilase/química , Lepidium sativum/crescimento & desenvolvimento , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Mostardeira/crescimento & desenvolvimento , Coelhos , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
The synthesis of antifungal natural product drimenal was accomplished. Bio-inspired optimization protruded chiral 8-(R)-drimane fused oxazinone D as a lead, considering favorable physicochemical profiles for novel pesticides. The improved scalable synthesis of scaffold D was implemented by Hofmann rearrangment under mild conditions. Detailed structural optimization was discussed for both antifungal and antibacterial exploration. Substituted groups (SGs) with C3â¼C5 hydrocarbon chain are recommended for exploration of antifungal agents, while substituents with C4â¼C6 carbon length are preferred for antibacterial ingredients. The chiral drimane fused oxazinone D8 was selected as a promising antifungal candidate against Botrytis cirerea, with an EC50 value of 1.18 mg/L, with the enhancement of up to >25 folds and >80 folds than the mother compound D, and acyclic counterpart AB5, respectively. The in vivo bioassay confirmed much better preservative effect of D8 than that of Carbendazim. The chiral oxazinone variant D10 possessed prominent antibacterial activity, with MIC values of 8 mg/L against both Bacillus subtilis and Ralstonia solanacearum, showing advantages over the positive control streptomycin sulfate.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Descoberta de Drogas , Oxazinas/farmacologia , Ralstonia solanacearum/efeitos dos fármacos , Sesquiterpenos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Bacillus subtilis/efeitos dos fármacos , Botrytis/efeitos dos fármacos , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazinas/química , Sesquiterpenos Policíclicos , Sesquiterpenos/química , Relação Estrutura-AtividadeRESUMO
A domino reaction sequence has been evaluated that begins with union of novel dihydrooxazinone precursors with 2-alkynyl-substituted benzaldehyde components through aldol condensation. Ensuing operations, including alkene isomerization, Diels-Alder, and retrograde Diels-Alder with loss of CO2 occurs in the same reaction vessel to provide polysubstituted tricyclic pyridine products.
RESUMO
A new family of cyclic carbamate-estradiol derivatives has been designed to remove the intrinsic estrogenic activity of a parent acyclic compound reported as a potent inhibitor of 17ß-hydroxysteroid dehydrogenase type 1 (17ß-HSD1). The synthesis of two series of fused 16ß,17ß-oxazinone-estradiol derivatives, saturated compounds 7a-d and unsaturated compounds 10a-d, led to the identification of 10b, a 17ß-HSD1 inhibitor (IC50 = 1.4 µM) without estrogenic activity in estrogen-sensitive T-47D cells. Interestingly, this compound was found selective over 17ß-HSD2 and 17ß-HSD12. A computational analysis of inhibitors into 17ß-HSD1 by molecular docking also revealed interesting structure-activity relationships that could be helpful in the design of new generation of 16ß,17ß-oxazinone-estradiol analogs.