Malaria is one of the most challenging diseases. Over three billion people are threatened by the parasite worldwide and one million is killed each year, mostly children. Plasmodium falciparum accounts for the most severe and fatal form of the disease. Adopting repurposing strategies for drug development, a series of novel tadalafil (an approved PDE5 inhibitor) analogues was rationally designed, synthesized, and evaluated as antimalarial agents. The novel analogues were designed to retain the tetrahydro-β-carboline nucleus of tadalafil, the pendant aryl benzodioxol was substituted by p-bromophenyl, p-chlorophenyl, 2,6 dichlorophenyl or 2,4 dimethoxyphenyl rings. Moreover, the N-methyl substituent of the piperazinedione ring was replaced by substituents namely: benzyl, 2,6 dichlorobenzyl, 2,6 difluorobenzyl or cyclohexylmethyl ring. Besides, we manipulated all stereochemical aspects via preparation of all possible diastereomers. The newly synthesized compounds were evaluated in vitro for their anti-plasmodial activity against P. falciparum using the Plasmodium lactate dehydrogenase (pLDH) assay and for their cytotoxicity against HeLa cells. Compound 3, the most active compound, showed IC₅₀ of 0.08 µM versus pLDH, CC₅₀ > 20 µM and SI₅₀ > 250, indicating a safe profile of most of the novel molecules. Whether the anti-plasmodial activity is facilitated via plasmodial PDE activity is still being investigated.