Heterocyclic compounds, such as hybrid tetrahydroquinoline and quinoline derivatives with phosphorated groups, have been prepared by multicomponent cycloaddition reaction between phosphorus-substituted anilines, aldehydes and styrenes. The antileishmanial activity of these compounds has been evaluated on both promastigotes and intramacrophagic amastigotes of Leishmania infantum. Good antileishmanial activity of functionalized tetrahydroquinolines 4a, 5a, 6b and quinoline 8b has been observed with similar activity than the standard drug amphotericin B and close selective index (SI between 43 and 57) towards L. infantum amastigotes to amphotericin B. Special interest shows tetrahydroquinolylphosphine sulfide 5a with an EC<sub>50</sub> value (0.61 ± 0.18 μM) similar to the standard drug amphotericin B (0.32 ± 0.05 μM) and selective index (SI = 56.87). In addition, compound 4c shows remarkable inhibition on Leishmania topoisomerase IB. Parallel theoretical study of stereoelectronic properties, application of docking-based virtual screening methods, along with molecular electrostatic potential and predictive druggability analyses are also reported.