title: Design, synthesis, and biological testing of thiosalicylamides as a novel class of calcium channel blockers.
abstract: The current research aimed to investigate the importance of the heterocyclic ring system in the structure of the cardiovascular drug diltiazem for its calcium channel blocking activity. The manuscript describes the design, synthesis, and biological testing of a total of 10 S-(p-methoxybenzyl), N-substituted thiosalicylamides as a series of non-cyclic compounds derived from diltiazem's structure. The new compounds maintained all diltiazem pharmacophores except the thiazepine ring system. In vitro evaluation of the new series for calcium channel blocking effects revealed moderate activities with IC50 values in the range of 4.8-56.0 microM. The data suggest that the ring system is not essential for activity; however, its absence leads to a considerable drop of activity relative to that of diltiazem (IC50=0.3 microM). Compounds of the current series showed optimum activity when the aliphatic alkyl chain on the salicylamide nitrogen is part of a piperidine or piperazine ring system substituted at the terminal nitrogen with a benzyl group.
authors.affiliation: Massachusetts College of Pharmacy and Health Sciences, 179 Longwood Ave, Boston, MA 02115, USA. ahmed.mehanna@bos.mcphs.edu
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Mehanna
authors.forename: Jin Yung
authors.initials: JY
authors.lastname: Kim
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015220:Calcium Channels / Q000737:chemistry; D004110:Diltiazem / Q000737:chemistry; D015195:Drug Design; D008297:Male; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012457:Salicylamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D010879:Piperazines; D010880:Piperidines; D012457:Salicylamides; D000077489:Piperazine; C032727:piperidine; D004110:Diltiazem