Design, Synthesis, and Pharmacological Evaluation of Conformationally Constrained Analogues of N,N‘-Diaryl- and N-Aryl-N-aralkylguanidines as Potent Inhibitors of Neuronal Na⁺ Channels

Abstract

In the present investigation, the rationale for the design, synthesis, and biological evaluation of potent inhibitors of neuronal Na+ channels is described. N,N'-diaryl- and N-aryl-N-aralkylguanidine templates were locked in conformations mimicking the permissible conformations of the flexible diarylguanidinium ion (AS+, AA+, SS+). The resulting set of constrained guanidines termed "lockamers" (cyclophane, quinazoline, aminopyrimidazolines, aminoimidazolines, azocino- and tetrahydroquinolinocarboximidamides) was examined for neuronal Na+ channel blockade properties. Inhibition of [14C]guanidinium ion influx in CHO cells expressing type IIA Na+ channels showed that the aminopyrimidazoline 9b and aminoimidazoline 9d, compounds proposed to lock the N,N'-diarylguanidinium in an SS+ conformation, were the most potent Na+ channel blockers with IC50's of 0.06 microM, a value 17 times lower than that of the parent flexible compound 18d. The rest of the restricted analogues with 4-p-alkyl substituents retained potency with IC50 values ranging between 0.46 and 2.9 microM. Evaluation in a synaptosomal 45Ca2+ influx assay showed that 9b did not exhibit high selectivity for neuronal Na+ vs Ca2+ channels. The retention of significant neuronal Na+ blockade in all types of semirigid conformers gives evidence for a multiple mode of binding in this class of compounds and can possibly be attributed to a poor structural specificity of the site(s) of action. Compound 9b was also found to be the most active compound in vivo based on the high level of inhibition of seizures exhibited in the DBA/2 mouse model. The pKa value of 9b indicates that 9b binds to the channel in its protonated form, and log D vs pH measurements suggest that ion-pair partitioning contributes to membrane transport. This compound stands out as an interesting lead for further development of neurotherapeutic agents.

A robust iron catalyst for the selective hydrogenation of substituted (iso)quinolones

“… 25 Notably, the more challenging lepidine substrate was also hydrogenated to the corresponding 1,2,3,4-tetrahydrolepidine ( 18 , 65%), which serves as a precursor for the synthesis of a central nervous system (CNS) depressant agent. 26 Furthermore, 2-(4-( tert -butyl)phenyl)-6-isopropyl-1,2,3,4-tetrahydroquinoline ( 19 ), a key intermediate for the synthesis of a neuronal Na + -channel antagonist, 27 was also afforded in high yield (93%). Interestingly, a quinoline substrate bioconjugated with (+)-α-tocopherol (vitamin E) was also successfully employed to furnish the selective hydrogenation product 20 in good yield (76%).…”

Synthesis of Novel Phosphorylated Guanidine Derivatives from Cyanamide and Their Anti-inflammatory Activity

“…Chemistry The synthesis of new biologically ac tive substituted N′-(2-thioxo-2,3-dihydro-2λ 5 -pyrido [2,3-d] [1,3,2] oxaza phosphol-2-yl) guanidine derivatives was accomplished in straight forward manner as shown in Chart 1. To synthesize target title derivatives, the key intermediate compound 4 was achieved in two steps.…”

“…To synthesize target title derivatives, the key intermediate compound 4 was achieved in two steps. First, the mono chloride interme diate, 2-chloro-2,3-dihydro-2λ 5 -pyrido [2,3-d] [1,3,2] oxaza phosphole-2-thione (3) was synthesized by reaction of 2-aminopyridin-3-ol (1) with thiophosphoryl chloride (2) in tetrahydrofuran (THF) using triethylamine (TEA) as mild base by stirring at room temperature for 3 h. The formation of monochloride 3 was ascertained by TLC eluting with a 3 : 2 mixture of ethyl acetate and hexane. After completion of the reaction, the resulting triethylamine hydrochloride (Et 3 N-HCl) was removed from the reaction mixture by filtration.…”

“…These have motivated the development of many reagents for their synthesis and various methods to achieve guanylation by nucleophilic addition of an amine to a cyanamide. 4) The guanidine derivatives exhibited diverse biological and pharmacological activities such as neuronal Na + and Ca 2+ channel blockers, 5) glutamate release inhibitors, anti-ischemic agents, 6) anti-seizure agents, 7) aderenergic neuron-blocking agents, 8) human immunodeficiency virus-1 (HIV-1) protease inhibitors, 9) K + /ATP channel openers, nitric oxide (NO) synthase inhibitors, influenza neuraminidase inhibitors, 10) cardiotonic agents, 11) and histamine H 3 receptor antagonists. 12) Therefore, the guanidine functional group is an attractive pharmacophore for the development of novel drugs against tumors, hypertension, glaucoma, and inflammation.…”

Synthesis of highly substituted tetrahydroquinolines using ethyl cyanoacetate via aza-Michael–Michael addition

“…Cascade or tandem reactions continue to be of interest because they offer a rapid and highly effective strategy for the synthesis of bioactive natural products [1][2][3][4][5] and pharmaceutical agents. [6][7][8][9][10][11][12][13][14][15][16] Tetrahydroquinolines have been targeted by many research groups because of their abundance in natural products and notable biological activity. Tetrahydroquinoline derivatives are used in pesticides, antioxidants, photosensitizers, and dyes in addition to pharmaceutical applications.…”