Ljubica GLAVAŠ OBROVAC, Vesna RASTIJA, Teuta OPAČAK BERNARDI, Ivana STOLIĆ, Luka KRSTULOVIĆ, Marijana JUKIĆ, Miroslav BAJIĆ

Investigation of the structural and physicochemical requirements of quinoline-arylamidine hybrids for the growth inhibition of K562 and Raji leukemia cells

Quantitative structure–activity relationship (QSAR) analysis of 28 quinoline-arylamidine (CQArA) hybridsagainst two leukemia cells, K562 and Raji, was performed. Multiple linear regression (MLR) models were obtained bygenetic algorithm. The best models involved the following descriptors: radial distribution function (RDF) descriptors,GETAWAY (GEometry, Topology, and Atom-Weights AssemblY) descriptor, bond information content index, and dipolemoment. The best MLR models for K562 and Raji cells demonstrated satisfactory stability in internal and externalvalidation. Since the QSAR model for Raji cells has better predictive ability, two new highly potent CQArA analogueswere proposed based on it. The QSAR models revealed important physicochemical and structural requirements for theantitumor activity: enhanced 3D molecular distribution of mass calculated at radius 11 Å from the center of molecule,a higher number of terminal electronegative atoms, extension of the molecules’ central linker between quinoline andarylamidine, higher ratio of single bonds and total number of atoms, and symmetric charge distribution. Moleculardocking study was applied to ensure the anticancer activity affinity to the binding site of the tyrosine-protein kinase(c-SRC). It was confirmed that the most active compound binds on the pocket between the small and large lobes ofc-SRC, mostly throughout the hydrogen bonds and van der Waals interactions.

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