Design, synthesis, and biological testing of thiosalicylamides as a novel class of calcium channel blockers

• Published in: Bioorganic & medicinal chemistry Vol. 13; no. 13; pp. 4323 - 4331
• Main Authors: Mehanna, Ahmed S., Kim, Jin Yung
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-07-2005; Elsevier Science
• Subjects: Animals; Aorta - drug effects; Biological and medical sciences; Calcium channel blockers; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - pharmacology; Calcium Channels - chemistry; Cardiovascular agents; Cardiovascular system; Diltiazem - chemistry; Drug Design; Male; Medical sciences; Miscellaneous; Molecular Structure; Pharmacology. Drug treatments; Piperazines - chemistry; Piperidines - chemistry; Rats; Rats, Wistar; Salicylamides - chemical synthesis; Salicylamides - chemistry; Salicylamides - pharmacology; Structure-Activity Relationship; Thiosalycilamides; Calcium channel blockers; Thiosalycilamides; Cardiovascular agents; Rat; Rodentia; Calcium antagonist; Cardiovascular disease; Diltiazem; In vitro; Modeling; Biological activity; Organic sulfide; Vertebrata; Mammalia; Animal; Blood vessel; Piperidine derivatives; Aorta; Carboxamide; Salicylamide; Piperazine derivatives; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.04.012

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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 IC
50 values in the range of 4.8–56.0
μM. 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 (IC
50
=
0.3
μM). 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.