Synthesis and sedative-hypnotic activity of helicid derivatives containing a 1,4-dihydropyridine moiety

Abstract

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...

7-(3-Nitrophenyl)-9,10-dihydro-7H-benzo[h]cyclopenta[b]quinolin-8(11H)-one

“…For the medicinal use of 1,4-dihydropyridine derivatives, see: Zheng et al (2011); Ginsberg & Kummer (2011);Nadaraj et al (2009) ;Husson et al (2011). For the preparation of the title compound, see: Heravi et al (2010).…”

“…The 1,4-dihydropyridine (1,4-DHP) derivatives exhibits various bioactivities, including sedative-hypnotic activity (Zheng et al 2011), inhibition of the α 4-integrin-paxillin interaction (Ginsberg et al 2011), anti-microbial activities (Nadaraj et al 2009),and antitumor activity (Husson et al 2011). These reports inspired us to study the relationship between their structures and activities.…”

Characterization of 1,4‐Dihydropyridine Derivatives by Electrospray Ionization Ion‐Trap Time‐of‐Flight Tandem Mass Spectrometry

“…As analogs of NADH coenzymes, 4‐substituted‐1,4‐DHP have become an important class of drugs that are potent calcium (Ca 2+ ) channel blockers. A recent computational analysis of the comprehensive medicinal chemistry database found that the DHP framework is among the most prolific chemotypes . Analogues of 1,4‐DHP derivatives can modulate the growth of human cells in vitro by mild oxidative stress, which can be convenient to further study oxidative homeostasis involving lipid peroxidation .…”