However, till 2010, there was no defined approach to combat EGFR resistance.

Therefore, steady and extended efforts were being undertaken for designing and

developing more potent and selective EGFR inhibitors. X Wu et al. designed and

synthesized two series of 4-benzothienyl amino quinazoline derivatives as new

analogues of gefitinib in 2010. A series of compounds were synthesized and

evaluated in comparison to parental gefitinib and the compounds with higher

selectivity and enhanced anti-EGFR activities were selected. The selected

compounds were compound 1 and compound 2 and are given in Table 21.1

(Wu et al. 2010; Ravez et al. 2015). Different series of quinazoline-based

compounds were designed using gefitinib as a reference. In the designed series,

benzene ring was substituted with a pyrrole ring. Taking gefitinib as a standard, the

synthesized compounds were evaluated for kinase inhibitory and antitumour

activities. Among a series of compounds, five compounds were significantly potent.

These five compounds are given in Table 21.1 as compounds 3–7. The structure-

activity analysis proposed that the anticancer activity of the compounds was raised

by replacing benzene ring attached to the 4-anilo nitrogen. Also, the anticancer

potential of the compounds was increased when position 6 or 7 was substituted or

branched with basic side chain (Ahmad 2017; Bhatia et al. 2020).

A novel series of quinazoline-based compounds was designed by X Qin et al. in

2016. The morpholin-3-one-fused quinazolines were synthesized by intramolecular

cyclization, and their anti-EGFR potential was evaluated. A compound with a tert-

butyl substituent on the lateral phenyl ring, a dimethoxyquinazolinyl moiety at

positions 6 and 7 and a benzylamino linker at position 3 showed the maximum

activity. Additionally, in silico studies revealed that the compound also had efficient

binding with the c-Raf (active site). The structural details of the compound are given

in Table 21.1 as compound 8 (Palumbo et al. 2016).

21.3

FDA-Approved Quinazoline-Based EGFR Inhibitors

21.3.1 Gefitinib

Gefitinib is a quinazoline-based small molecule EGFR inhibitor. It was approved by

the FDA in 2003 for the treatment of NSCLC. It was the first FDA-approved

quinazoline-based EGFR inhibitor. Gefitinib acts by binding to the active conforma-

tion of EGFR. The chemical structure of the drug is given in Fig. 21.2. Gefitinib is

administered through oral route and is absorbed with a mean bioavailability of 60%.

The volume of distribution of the drug is very high (1400:1) and thus is distributed

through the body tissues such as the kidney, liver, lungs and tumours. The drug

reaches to its peak level from 3 to 7 h with a mean elimination half-life of 48 h. After

getting absorbed in the blood, 90% of the drug binds to the serum albumin and α1-

acid glycoproteins. CYP3A4 is involved in the hepatic metabolism of the drug. This

enzyme biotransforms the drug by demethylating the methoxy substituent,

metabolizing the N-propoxymorpholino group and by oxidative defluorination of

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