Exploration of Chemical Space Based on 4-Anilinoquinazoline

Abstract

Chemical space is defined as all possible small organic molecules, including those present in biological systems, which is so vast that so far only a tiny fraction of it has been explored. Indeed, a thorough examination of all "chemical space" is practically impossible. The success of three EGFR inhibitors (Gefitnib, Erlotinib, Lapatinib) suggests that 4-anilinoquinazoline scaffold is still worth developing in the future. To date hundreds of this sort of derivatives have been synthesized and show potent anticancer activities. Most of the compounds have been proved to be EGFR/HER2 kinase inhibitors, binding at the hinge region of the ATP site and some lead compounds have been optimized against a number of different kinases, including VEGFR-2, Src, Aurora A/B, Tpl, Clk and PDE10A. Now there is now a rich pipeline of novel anticancer agents based on 4-anilinoquinazoline in early phase clinical trials. This review will highlight the exploration of chemical space of 4-anilinoquinazoline in the past ten years and we hope that increasing knowledge of the SAR and cellular processes underlying the antitumor-activity of anilinoquinazoline derivatives will be beneficial to the rational design of new generation of small molecule anticancer drugs.

Optimization of Substituted 6-Salicyl-4-Anilinoquinazoline Derivatives as Dual EGFR/HER2 Tyrosine Kinase Inhibitors

“…Since 4-anilinoquinazoline analogs exhibited widely kinase inhibitions [26], the selectivity profile of compound 21 was assessed against several key kinases close to EGFR/HER2 (Figure 6B, for detailed data please see Table S1). The data confirmed the generally good selectivity profile of 21 but also identified some activity against CDK2, with an IC 50 value of 3.5 µ M. In general, compound 21 bearing a trifluoromethyl group at the 4-position of the salicylic ring, which was proposed to fit the ATP binding pocket very well, showed more than 100-fold selectivity against major of other kinases screened.…”

An appraisal of anticancer activity with structure–activity relationship of quinazoline and quinazolinone analogues through EGFR and VEGFR inhibition: A review

“…Thus, the focus on 4‐anilinoquinazoline will continue to find more active inhibitors of receptor tyrosine kinase. Other quinazoline derivatives like benzo‐quinazoline, cinnamide quinazoline, or hybrids of quinazoline with thiophene, triazine, and imidazole were found very promising in terms of EGFR inhibitory activity (Bhatia et al, 2020; Das et al, 2020; Li et al, 2012; Y.‐J. Liu et al, 2012).…”

“…Quinazoline and quinazolinone heterocycle‐based compounds have shown promising development as tubulin inhibitors, a polo‐like kinase inhibitor, EGFR inhibitor, and VEGFR inhibitor. Most of the quinazoline or quinazolinone‐based compounds exhibited potent inhibitory potency with efficacy in the nano‐molar range against EGFR and VEGFR kinases and several cancer cell lines (Bhatia et al, 2020; Das et al, 2020; Kavitha et al, 2018; Li et al, 2012; Liu et al, 2012; Srivastava et al, 2012).…”

Benzoquinoline Chemical Space: A Helpful Approach in Antibacterial and Anticancer Drug Design

“…Exploration of the chemical space is performed by using in silica databases of virtual molecules, visualized by projecting the multidimensional molecular property space in lower dimensions, characterized by physicochemical measurable/quantifiable properties. As stated before, the generation of valid chemical structures using any means (experimental or in silica) leads to novel compounds [ 25 , 26 , 27 , 28 ]. Moving through the chemical space is performed by generating stoichiometric combinations of 12 electrons (all stoichiometric inorganic materials) and atomic nuclei to approach all possible topology isomers to give construction rules.…”