Síntesis, caracterización química y modelado molecular de la 3-[(7 - cloroquinolin - 4 - il) amino] acetofenona

Abstract

Malaria is a disease that causes problems worldwide, caused by the Plasmodium parasite. Most deaths are associated with P. falciparum. One of the new therapeutic targets being evaluated for the treatment of malaria is the inhibition of hemozoin, since inhibiting the formation of hemozoin frees the heme groups produced during the parasite's life cycle, making them toxic to the parasite itself and causing its death. P. falciparum lactate dehydrogenase (pfLDH) plays a key role in this process. Several drugs are used to treat the disease; however, due to their indiscriminate use, they have caused resistance, reducing their potential and selectivity. The development of chloroquinoline derivatives attempts to combat this problem through pharmacomodulation of the properties of the quinoline nucleus. To obtain 3-[(7-chloroquinolin-4-yl)amino]acetophenone, a condensation reaction was carried out by aromatic nucleophilic substitution, yielding a pale yellow crystal with a melting point of 294°C and a reaction yield of 98%. Subsequently, chemical characterization was performed using spectroscopic techniques and single crystal X-ray diffraction, confirming the structure of the compound and the presence of impurities. In addition, a molecular modeling process was carried out to identify the molecular characteristics of the compound and compare them with Lipinski and Veber's rules, identifying that the compound can be considered as a leading compound for drug development. Finally, a prediction was made of the compound's binding sites with pfLDH, identifying the binding with three amino acid residues: Arginine 171, Tyrosine 247, and Valine 248. The binding with these residues predicts competitive inhibition of the pfLDH binding site with NAD+, which causes inhibition of hemozoin formation