“…[12,13] However, early Phase I clinical trials of third-generation EGFR inhibitors are found to be promising and effective, but they are likely to produce off-target side-effects and toxicities after their prolonged use. [14,15] Thus, based on our previous experiences in anticancer drug discovery, [16][17][18][19][20][21][22][23][24] we have designed the target compounds (Figure 2) considering the common pharmacophoric features of erlotinib (reversible) and WZ4002 (irreversible) [25] with the assumptions that compounds should: (a) possess pyrimidine ring with 2-alkoxy/ hydroxyl aniline moiety for hydrogen bond interaction with MET793, (b) be able to selectively target hypoxic tumours by possessing nitro substituent on either or both the aromatic rings with/without solubility enhancer due to their bioreduction to yield electrophilic substances which are capable of damaging protein and nucleic acids [24,26] and have radiosensitizing ability, [27] (c) be reversible and non-covalent in nature as irreversible inhibitors not only make covalent interactions with CYS797 of target but also undergo conjugate addition with other nucleophiles in the body due to their Michael acceptor property, thereby leading to off-target side-effects and, (d) be easy to synthesize and cost-effective.…”