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A quantitative structure-activity relationship (QSAR) study was conducted using nineteen previously synthesized, and tested 1-aryl-6-hydroxy-1,2,3,4-tetrahydroisoquinolines with proven in vitro activities against Plasmodium falciparum . In order to computationally design and screen potent antimalarial agents, these compounds with known biological activity ranging from 0.697 to 35.978 μM were geometry optimized at the B3LYP/6-311 + G(d,p) level of theory, using the Gaussian 09W software. To calculate the topological differences, the series of the nineteen compounds was superimposed and a hypermolecule obtained with s ¯ = 17 and 20 vertices. Other molecular descriptors were considered in order to build a highly predictive QSAR model. These include the minimal topological differences (MTD), LogP, two dimensional polarity surface area (TDPSA), dipole moment (μ), chemical hardness (η), electrophilicity (ω), potential energy (E p ), electrostatic energy (E ele ) and number of rotatable bonds (NRB). By using a training set composed of 15 randomly selected compounds from this series, several QSAR equations were derived. The QSAR equations obtained were then used to attempt to predict the IC 50 values of 4 remaining compounds in a test (or validation) set. Ten analogues were proposed by a fragment search of a fragment library containing the pharmacophore model of the active compounds contained in the training set. The most active proposed analogue showed a predicted activity within the lower micromolar range., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)