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The in vitro activity of the first-generation IVM\u00a0hybrids synthesized by appending the IVM macrolide with heterocyclic and organometallic antimalarial pharmacophores, against the blood-stage and liver-stage infections by <jats:italic>Plasmodium<\/jats:italic> parasites prompted us to design second-generation molecular hybrids of IVM. Here, a structural modification of IVM\u00a0to produce novel molecular hybrids by using sub-structures of 4- and 8-aminoquinolines, the time-tested antiplasmodial agents used for treating the blood and hepatic stage of <jats:italic>Plasmodium<\/jats:italic> infections, respectively, is presented. Successful isolation of regioisomers and epimers has been demonstrated, and the evaluation of their in vitro antiplasmodial activity against both the blood stages of <jats:italic>P. falciparum<\/jats:italic> and the hepatic stages of <jats:italic>P. berghei<\/jats:italic> have been undertaken. These compounds displayed structure-dependent antiplasmodial activity, in the nM range, which was more potent than that of IVM, its\u00a0aglycon or primaquine, highlighting the superiority of this hybridization strategy in designing new antiplasmodial agents.<\/jats:p>","DOI":"10.1038\/s41598-021-04532-w","type":"journal-article","created":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T11:02:59Z","timestamp":1641985379000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Synthesis and antiplasmodial activity of regioisomers and epimers of second-generation dual acting ivermectin hybrids"],"prefix":"10.1038","volume":"12","author":[{"given":"Lovepreet","family":"Singh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Fontinha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denise","family":"Francisco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel","family":"Prud\u00eancio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamaljit","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,1,12]]},"reference":[{"key":"4532_CR1","doi-asserted-by":"publisher","first-page":"17050","DOI":"10.1038\/nrdp.2017.50","volume":"3","author":"MA Phillips","year":"2017","unstructured":"Phillips, M. 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