Reactions of natural helicid with a number of 1,3-dicarbonyl compounds or E-ketoester in the presence of ammonium acetate or 1-naphthylamine gave a series of helicid derivatives containing a 1,4-dihydropyridine fragment (2a-2h). Eight novel helicid derivatives were structurally confirmed by IR, 1 H NMR, 13 C NMR, and HR-MS spectroscopy and evaluated for their sedative-hypnotic activities on mice. The results demonstrated that two compounds had higher sedative-hypnotic activity compared with helicid.Helicid (1, 4-formylphenyl-E-D-allopyranoside), is originally isolated from the fruit of Helicia nilagirica Beed [1], a plant indigenous to western China. Owing to a rare allopyranoside, it has a variety of biological activities on the central nervous system such as sedative, hypnotic, and anticonvulsant activities [2]. However, its long onset time and low bioavailability prompted us to search for new derivatives of helicid through structure modifications [3][4][5][6][7].1,4-Dihydropyridines (1,4-DHPs) are among the most widely used drugs for the management of cardiovascular disease [8], which have a broad range of other pharmacological activities, such as antitumor, bronchodilating, antidiabetic, and antiviral [9-12]. 4-Substituted 1,4-dihydropyridines are analogs of NADH coenzymes and an important class of drugs that are potent blockers of calcium (Ca 2+ ) current. A recent computational analysis of the comprehensive medicinal chemistry database found the DHP framework to be among the most prolific chemotypes. From the viewpoint of molecular design, to construct a dual-target drug molecule, a connective molecule can simply be realized by combining two active molecules or their pharmacophores with a linker, while an integrated molecule comes into an entity either by fusing or by merging the common structural or pharmacophoric features of two active molecules, depending on the extent of the common features. This approach facilitates the reduction of molecular size and molecular weight and the optimal overlap between the pharmacodynamic and pharmacokinetic spaces, which will certainly elevate its probability of being a drug. Thus, based on our high throughout work on the structure-activity relationship of helicid, we designed and synthesized eight helicid derivatives containing the DHP framework through the reactions shown in Scheme 1, with the aim to explore new drugs with superior bioactivity and better efficacy [13][14][15]. Pharmacological test showed that compounds 2a and 2h displayed promising sedative-hypnotic activity superior to helicid (Table 1). So, further modification of helicid should be worthwhile.The most common route for the synthesis of 1,4-dihydropyridines is the Hantzsch reaction. It is the condensation of a E-ketoester or 1,3-dicarbonyl compound with an aldehyde and ammonia or primary amine either in acetic acid or by refluxing in alcohol. However, the reaction times for 6-72 h are too long and the yields are generally low. Therefore, in our preliminary study, a series of helicid derivatives 2a-2e w...
Seven helicid derivatives containing decahydroacridine-1,8-dione were prepared via the reactions between 1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione and the corresponding Schiff base. The structures of the helicid derivatives were characterized by IR, 1 H NMR, and HR-MS spectrum. The target compounds were evaluated by their hypnotic-sedative activity in vivo. The preliminary bioassay tests showed that some of the compounds had more potent activity than that of helicid.Insomnia is a worldwide health problem. Improvements in the treatment of insomnia and its syndrome have already ameliorated sleeping of the insomniac, but the number of new insomniacs continues to rise. Thus, useful drugs with few side effects are required to treat the entire insomnia syndrome.The natural compound helicid [4-formylphenyl-E-D-allopyranoside, C 13 H 16 O 7 ], originally extracted from the fruit of Helicia nilagirica Beed [1], has a variety of biological activities on the central nervous system owing to a rare form of allopyranoside. These activities include hypnotic, anti-inflammatory, and anticonvulsant activities [2]. However, its long onset time and low bioavailability limits the scope of clinical application. As part of our efforts to discover new hypnotic-sedative agents, we have synthesized a series of helicid derivatives by introducing the decahydroacridine-1,8-dione framework, which plays an important role in the regulation of different calcium channels [3][4][5][6].The synthesis pathway leading to the title compounds is given in Scheme 1. Treatment of commercially available helicid with appropriate primary amines in the presence of ethanol solvent provided the corresponding Schiff base. By adding 1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione to the unpurified Schiff base, we achieved intramolecular cyclization in the target compounds [7][8][9][10]. O OH OH HO O CHO HOH 2 C a O OH OH HO O CH NR 1 HOH 2 C O OH OH HO O NR 1 O R 2 R 2 R 2 R 2 O HOH 2 C b 2a -2g2a: R 1 = CH 3 , R 2 = H, 2b: R 1 = CH 2 CH 3 , R 2 = H, 2c: R 1 = CH 2 CH 2 CH 3 , R 2 = H, 2d: R 1 = p-CH 3 C 6 H 4 , R 2 = H 2e: R 1 = C 6 H 5 , R 2 = H, 2f: R 1 = CH 3 , R 2 = CH 3 , 2g: R 1 = CH 2 CH 3 , R 2 = CH 3 a. R 1 NH 2 , CH 3 CH 2 OH, reflux, 4h, helicid : R 1 NH 2 (1:2); b. 1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione, CH 3 CH 2 OH, reflux, 10 h. Scheme 1. Synthesis of compounds 2a-2g.
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