Synthesis, Molecular Modeling, Anticonvulsant and Antinociceptive Properties of New 1,1‐Disubstituted Cyclohexane and 1,3‐Diazaspiro[4.5]decane Derivatives

Abstract

The current work describes the synthesis of new series of N-(1-(cyclohexylcarbamoyl) cyclohexyl)-N-phenylarylamides (10 a-h) and 3-cyclohexyl-1,2-diphenyl and 2-(substituted phenyl)-1,3diazaspiro[4.5]decanes (12 a-h).The new compounds were screened for their anticonvulsant and antinociceptive activities using sodium valproate and tramadol hydrochloride, respectively as reference standards. 4-Chloro-N-(1-(cyclohexylcarbamoyl)cyclohexyl)-N-phenylbenzamide (10 b), 3-Cyclohexyl-1,2diphenyl-1,3-diazaspiro[4.5]decane (12 a) and 3-Cyclohexyl-1phenyl-2-(3,4,5-trimethoxyphenyl)-1,3-diazaspiro[4.5]decane (12 d) showed higher anticonvulsant activity than sodium valproate at dose 0.08 mmol/kg. On the other hand, 4-Amino-N- (1-(cyclohexylcarbamoyl) cyclohexyl)-N-phenylbenzamide (10 h) and 3-Cyclohexyl-1-phenyl-2-(3,4,5-trimethoxyphenyl)-1,3-diazaspiro[4.5]decane (12 d) exhibited higher antinociceptive potential in both intensity and duration than tramadol hydrochloride. The pharmacokinetics of the new compounds were calculated in-silico. Additionally, 3D pharmacophoric model was generated.[a] Prof.

Design, synthesis, and biological evaluation of new pyrimidine-5-carbonitrile derivatives as novel anti-cancer, dual EGFRWT/COX-2 inhibitors with docking studies

“…Topological polar surface area, or TPSA, measures a molecule's capability for intestinal absorption; a TPSA value less than 140 is required. 48 The TPSA range for all newly synthesized compounds in this study is between 74.87 to 133.16. The GI absorption is high in all tested compounds except 3c and 4c.…”

Anticonvulsant Classes and Possible Mechanism of Actions

“…As a contribution to this field on the search for new anticonvulsant candidates, herein is reported the synthesis of compounds 9, 10, and 11, where a design modification of compounds 7 and 8 was considered in which the amino moiety [A] linked to the methylene cyclohexyl scaffold is replaced by cyclohexyl carboxamide, 110 in the same way as synthesis of certain (1-(benzyl(aryl)amino)cyclohexyl) methyl ester derivatives 12 111 and N-(1-(cyclohexylcarbamoyl)cyclohexyl)-N-phenylarylamides 13 (Figure 17). 112 Valproic acid is among the most frequently prescribed medications for the treatment of epilepsy. The uncomplicated composition of short-branched fatty acids is notably distinct from the complex substituted heterocyclic ring structures that are atypical of conventional antiepileptic drugs (Figure 18).…”