Molecular Parameters and Structure Activity Relationship towards Mexican Leishmania of 3-Carboethoxy-4-Amino Quinolines.

Resume Some quinolines and related compounds are known to be active as antiparasitic, antihypertensive, and antitumor agents. One of the proposed mechanisms is the intercalative interaction or not with DNA segments. This interaction has been demonstrated by NMR, UV-visible and computational methods. This work presents a computational study to elucidate essential structural elements for pharmacological activity, in a set of compounds that includes known antimalarial drugs: 2,4-diamino-6,7-dimethoxyquinoline (DDQ), amodiaquine, chloroquine, and a series of 3-carboethoxy-4-N-alkylaminoquinolines synthesized in our laboratories and whose biological activity towards Lehismania mexicana we determined. Energetically accessible conformations of the series of compounds were generated and geometrically optimized using molecular dynamics (MM+) and minimization (simulated annealing) and later optimized for the calculation of electronic properties using the AM1 semi-empirical method. Molecular properties were calculated including electrostatic potential maps, HOMO-LUMO energies, dipole moments, heats of formation, charge density (Mülliken), solvation energy, octanol-water partition coefficient (log P), polarizability, hardness, surface area. , volume and thermodynamic parameters, using the AM1 Hamiltonian model in order to identify properties that can be correlated with biological activity. Pharmacophore models are proposed based on the identification of common structural patterns, both for antimalarial drugs and for the group of 3-carboethoxy-4-N-alkylaminoquinolines whose activity against Lehismania mexicana was determined. The proposed pharmacophore models will serve as the basis for molecular design in the search for new drugs with the desired activity.