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The search for quality hits has been challenging as many inhibitory molecules may not progress to the next development stage. The aim of this work was to screen an in-house library of heterocyclic compounds (HCUV) for antimalarial activity combining computational predictions and phenotypic techniques to find quality hits. The physicochemical determinants, pharmacokinetic properties (ADME), and drug-likeness of HCUV were evaluated in silico, and compounds were selected for structure-based virtual screening and in vitro analysis. Seven <jats:italic>Plasmodium<\/jats:italic> target proteins were selected from the DrugBank Database, and ligands and receptors were processed using UCSF Chimera and Open Babel before being subjected to docking using Autodock Vina and Autodock 4. Growth inhibition of <jats:italic>P. falciparum<\/jats:italic> (3D7) cultures was tested by SYBR Green assays, and toxicity was assessed using hemolytic activity tests and the <jats:italic>Galleria mellonella<\/jats:italic> in vivo model. From a total of 792 compounds, 341 with good ADME properties, drug-likeness, and no interference structures were subjected to in vitro analysis. Eight compounds showed IC<jats:sub>50<\/jats:sub> ranging from 0.175 to 0.990\u00a0\u00b5M, and active compounds included pyridyl-diaminopyrimido-diazepines, pyridyl-N-acetyl- and pyridyl-N-phenyl-pyrazoline derivatives. The most potent compound (UV802, IC<jats:sub>50<\/jats:sub> 0.178\u00a0\u00b5M) showed no toxicophoric and was predicted to interact with <jats:italic>P. falciparum<\/jats:italic> 1-cysperoxidredoxin (<jats:italic>Pf<\/jats:italic>Prx1). For the remaining 7 hits (IC<jats:sub>50<\/jats:sub>\u2009&lt;\u20091\u00a0\u03bcM), 3 showed in silico binding to <jats:italic>Pf<\/jats:italic>Prx1, one was predicted to bind the haloacid dehalogenase-like hydrolase and plasmepsin II, and one interacted with the plasmodial heat shock protein 90.<\/jats:p>","DOI":"10.1007\/s00436-023-08089-7","type":"journal-article","created":{"date-parts":[[2023,12,29]],"date-time":"2023-12-29T04:44:51Z","timestamp":1703825091000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["In silico prediction and in vitro assessment of novel heterocyclics with antimalarial activity"],"prefix":"10.1007","volume":"123","author":[{"given":"Martha Ilce","family":"Orozco","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro","family":"Moreno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel","family":"Guevara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodrigo","family":"Abonia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jairo","family":"Quiroga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Braulio","family":"Insuasty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mauricio","family":"Barreto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Elena","family":"Burbano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2160-5167","authenticated-orcid":false,"given":"Maria del Pilar","family":"Crespo-Ortiz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,12,29]]},"reference":[{"key":"8089_CR1","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.ejmech.2009.10.023","volume":"45","author":"B Acharya","year":"2010","unstructured":"Acharya B, Saraswat D, Tiwari M, Kumar A (2010) Synthesis and antimalarial evaluation of 1, 3, 5-trisubstituted pyrazolines. 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