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2-Arylquinazolines with a range of alkyl polyamines as side chain/ring functional motifs at the 4th-position were considered for antileishmanial study with the rationale that related heterocyclic scaffolds and polyamine functionalities are present in drugs, clinical trial agents, natural products and anti-parasitic/leishmanial agents. Synthesis involves construction of the 2-arylquinazolin-4-one ring and deoxyamination viadeoxychlorination followed by SNAr-based amination or a methodology of SNAr–deoxyamination driven by BOP-mediated hydroxyl-activation. Various alkyl-polyamines important for activities were incorporated. A total of 26 compounds were prepared and screened against Leishmania donovani(Ld) promastigote cells using the MTT assay. Most of the investigated series of compounds showed characteristic leishmanicidal properties. Several compounds showed pronounced leishmanicidal activities (IC50: 5–6.5 μM) with higher efficiency than the antileishmanial drug miltefosine (IC50: 10.5 μM), and relatively less cytotoxicity to macrophage host cells (SI: 9.27–13.5) compared to miltefosine (SI: 3.42). Important pharmacophoric skeletons were identified.