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One-Pot Multicomponent Synthesis of Methoxybenzo[h]quinoline-3-carbonitrile Derivatives; Anti-Chagas, X-ray, and In Silico ADME/Tox Profiling Studies.

ABSTRACT: Several methoxybenzo[h]quinoline-3-carbonitrile analogs were designed and synthesized in a repositioning approach to developing compounds with anti-prostate cancer and anti-Chagas disease properties. The compounds were synthesized through a sequential multicomponent reaction of aromatic aldehydes, malononitrile, and 1-tetralone in the presence of ammonium acetate and acetic acid (catalytic). The effect of the one-pot method on the generation of the target product has been studied. The compounds were in vitro screened against bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and were most effective at showing a better activity profile than nifurtimox and benznidazole (reference drugs). A study in silico on absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) profiling to help describe the molecular properties related to the pharmacokinetic aspects in the human body of these compounds was reported. In addition, X-ray data for the compound 2-Amino-5,6-dihydro-4-(3-hydroxy-4-methoxy-phenyl)-8-methoxybenzo[h]quinoline-3-carbonitrile 6 was being reported. Spectral (IR, NMR, and elemental analyses) data on all final compounds were consistent with the proposed structures.

SUBMITTER: Ramirez H

PROVIDER: S-EPMC8619670 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The abnormal expression of the c-Met tyrosine kinase has been linked to the proliferation of several human cancer cell lines, including non-small-cell lung cancer (NSCLC). In this context, the identification of new c-Met inhibitors based on heterocyclic small molecules could pave the way for the development of a new cancer therapeutic pathway. Using multiple linear regression (MLR)-quantitative structure-activity relationship (QSAR) and artificial neural network (ANN)-QSAR modeling techniques, we look at the quantitative relationship between the biological inhibitory activity of 40 small molecules derived from cyclohexane-1,3-dione and their topological, physicochemical, and electronic properties against NSCLC cells. In this regard, screening methods based on QSAR modeling with density-functional theory (DFT) computations, in silico pharmacokinetic/pharmacodynamic (ADME-Tox) modeling, and molecular docking with molecular electrostatic potential (MEP) and molecular mechanics-generalized Born surface area (MM-GBSA) computations were used. Using physicochemical (stretch-bend, hydrogen bond acceptor, Connolly molecular area, polar surface area, total connectivity) and electronic (total energy, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels) molecular descriptors, compound 6d is identified as the optimal scaffold for drug design based on in silico screening tests. The computer-aided modeling developed in this study allowed us to design, optimize, and screen a new class of 36 small molecules based on cyclohexane-1,3-dione as potential c-Met inhibitors against NSCLC cell growth. The in silico rational drug design approach used in this study led to the identification of nine lead compounds for NSCLC therapy via c-Met protein targeting. Finally, the findings are validated using a 100 ns series of molecular dynamics simulations in an aqueous environment on c-Met free and complexed with samples of the proposed lead compounds and Foretinib drug.

Dataset Information

One-Pot Multicomponent Synthesis of Methoxybenzo[h]quinoline-3-carbonitrile Derivatives; Anti-Chagas, X-ray, and In Silico ADME/Tox Profiling Studies.

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