Antiproliferative and Trypanocidal Activity of Ivermectin Bioconjugates

Abstract

Ivermectin (IVR), whose discovery has been Nobel-Prize-honored, is a 16-membered macrocyclic lactone used in medicine as an extremely effective and safe antiparasitic drug. In recent years, interest in this compound has grown due to its potential effectiveness in killing various types of cancer cells. However, research on the anticancer activity of IVR derivatives is limited. Additionally, the growing problem of drug resistance raises concerns about the effectiveness of this drug in the treatment of parasitic diseases. Therefore, in this work, we provide a detailed description of the synthesis of ten new IVR bioconjugates with compounds exhibiting high anticancer and/or antimicrobial activity. We also assess the effectiveness of these hybrids in killing Trypanosoma brucei brucei a protozoan parasite that causes African trypanosomiasis, as well as their anticancer activity toward various cancer cell lines. Many of the newly synthesized conjugates exhibited higher biological activity than their respective parent compounds as well as increased selectivity indices. The IVR conjugate with artesunate (compound 16) appears particularly interesting, as it proved not only to be several times more active than the parent compounds but also showed no toxicity toward a reference cell line, indicating its potential as a therapeutic agent.

1

Chemical structure of ivermectin (IVR), its C13-hybrid with a chloroquine analog, and the C13-hybrid of IVR and artesunate studied in this work.

1. Synthesis of N-Deacetylthiocolchicine

2. Synthesis of Bioconjugates of IVR with Cinchona Bark Alkaloids and N-Deacetylthiocolchicine

3. Synthesis of Bioconjugates of IVR with Nucleoside Analogs (Floxuridine and Azidothymidine) and Metronidazole

4. Synthesis of Propargyl Esters of Betulinic Acid and Artesunate

5. Synthesis of Bioconjugates of IVR with Betulinic Acid and Artesunate