Enzymatic synthesis of amlodipine amides and evaluation of their anti-Trypanosoma cruzi activity

Advancing with our project about the development of new antiparasitic agents, we have enzymatically synthesized a series of amides derived from amlodipine, a calcium channel blocker used as an antihypertensive drug. Through lipase-catalyzed acylation with different carboxylic acids, nineteen amlodipine derivatives were obtained, eighteen of which were new compounds. To optimize the reaction conditions, the influence of several reaction parameters was analyzed, finding different requisites for aliphatic carboxylic acids and phenylacetic acids. All synthesized compounds were evaluated as antiproliferative agents against Trypanosoma cruzi, the etiological agent of American trypanosomiasis (Chagas' disease). Some of them showed significant activity against the amastigote form of T. cruzi, the clinically relevant form of the parasite. Among synthesized compounds, the derivatives of myristic and linolenic acids showed higher efficacy and lower cytotoxicity. These results added to the advantages shown by the enzymatic methodology, such as mild reaction conditions and low environmental impact, making this approach a valuable way to synthesize these amlodipine derivatives with an application as promising antiparasitic agents.

Automated summary

In our project on developing new antiparasitic agents, we synthesized a series of amides derived from amlodipine, a calcium channel blocker used as an antihypertensive drug, through enzymatic synthesis. By using lipase-catalyzed acylation, we obtained nineteen amlodipine derivatives, with eighteen of them being new compounds. The synthesized compounds were evaluated for antiproliferative activity against Trypanosoma cruzi, the causative agent of Chagas' disease, and some of them showed significant activity against the clinically relevant form of the parasite. The derivatives of myristic and linolenic acids demonstrated the highest efficacy and lowest cytotoxicity among the synthesized compounds. The enzymatic methodology used in this study offers mild reaction conditions and low environmental impact, making it a valuable approach for synthesizing promising antiparasitic agents based on amlodipine.