DFT investigations on arylsulphonyl pyrazole derivatives as potential ligands of selected kinases

Kornelia Czaja,Radosław Kujawski,Marek K Bernard,Jacek Kujawski

doi:10.1515/chem-2020-0135

Kornelia Czaja, Radosław Kujawski + Show 2 more

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https://doi.org/10.1515/chem-2020-0135

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Journal: Open Chemistry	Publication Date: Aug 3, 2020
Citations: 6	License type: CC BY 4.0

Affiliation: Poznan University of Medical Sciences

Abstract

AbstractUsing the density functional theory (DFT) formalism, we have investigated the properties of some arylsulphonyl indazole derivatives that we studied previously for their biological activity and susceptibility to interactions of azoles. This study includes the following physicochemical properties of these derivatives: electronegativity and polarisability (Mulliken charges, adjusted charge partitioning, and iterative-adjusted charge partitioning approaches); free energy of solvation (solvation model based on density model and M062X functional); highest occupied molecular orbital (HOMO)–lowest occupied molecular orbital (LUMO) gap together with the corresponding condensed Fukui functions, time-dependent DFT along with the UV spectra simulations using B3LYP, CAM-B3LYP, MPW1PW91, and WB97XD functionals, as well as linear response polarisable continuum model; and estimation of global chemical reactivity descriptors, particularly the chemical hardness factor. The charges on pyrrolic and pyridinic nitrogen (the latter one in the quinolone ring of compound 8, as well as condensed Fukui functions) reveal a significant role of these atoms in potential interactions of azole ligand–protein binding pocket. The lowest negative value of free energy of solvation can be attributed to carbazole 6, whereas pyrazole 7 has the least negative value of this energy. Moreover, the HOMO–LUMO gap and chemical hardness show that carbazole 6 and indole 5 exist as soft molecules, while fused pyrazole 7 has hard character.

Highlights

Pyrazole and indazole derivatives can act as bioisosteric mimics for some important natural compounds, namely, pyrrole, indole, and purine
Indazole derivatives 1–6 and condensed pyrazoles 7 and 8 (Scheme 1) were initially optimised by molecular mechanics, a series of 1,000 conformers for each azole derivative were further refined by the semiempirical method PM7
The molecular electrostatic potential (MEP) was determined by the B3LYP/6-311++G(2d,3p) approach for the conformers of azoles 1–8 with geometry previously optimised at the

Summary

Introduction

Pyrazole and indazole derivatives can act as bioisosteric mimics for some important natural compounds, namely, pyrrole, indole, and purine They display a broad spectrum of pharmacological activities and are present in many currently available drugs [1,2], including anticancer agents such as axitinib, crizotinib, pazopanib, ruxolitinib, ibrutinib, and niraparib [3,4]. Pazopanib is an indazolylpyrimidine derivative active orally It is a potent and selective multitargeted inhibitor of VEGFR 1, VEGFR 2, VEGFR 3, PDGFR, and c Kit kinase that blocks tumour growth and angiogenesis [9].

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