Details

Autor(en) / Beteiligte

• Kardile, Ramakant A.
• Sarkate, Aniket P.
• Lokwani, Deepak K.
• Tiwari, Shailee V.
• Azad, Rajaram
• Thopate, Shankar R.

Titel

Design, synthesis, and biological evaluation of novel quinoline derivatives as small molecule mutant EGFR inhibitors targeting resistance in NSCLC: In vitro screening and ADME predictions

Ist Teil von

• European journal of medicinal chemistry, 2023-01, Vol.245 (Pt 1), p.114889-114889, Article 114889

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• Here in, we report the design, synthesis and in vitro anticancer activity of a novel series of 24 quinoline analogues of substituted amide and sulphonamide derivatives. The anticancer activity of the synthesised compounds was evaluated against the HCC827, H1975 (L858R/T790 M), A549 (WT EGFR), A-549 and BEAS-2B cell lines. The majority of quinoline compounds demonstrated a significant cytotoxic effect. Compound 21 was found to be the most potent, with IC50 values of 0.010 μM, 0.21 μM, 0.99 μM and 2.99 μM as compared to Osimertinib with IC50 values with of 0.0042 μM, 0.04 μM, 0.92 μM and 2.67 μM. Compound 21 exhibited promising inhibitory enzymatic activity against the EGFR L858R/T790 M with IC50 value of 138 nM, comparable to Osimertinib's 110 nM. Employing a Western blot assay on the phosphorylation of EGFR and the signalling pathways transmission in HCC827 cells, the anticancer activity of the synthesised compounds 18 and 21 was evaluated in terms of its mechanism of action. All the compounds were subjected to a comparative molecular docking study against various EGFR enzyme types, including the wild-type (PDB: 4I23) and T790 M mutant (PDB: 2JIV) enzymes. Furthermore, compounds were examined at the allosteric binding site of the EGFR enzyme with the L858R/T790 M/C797S mutation (PDB ID: 5D41). The MD simulation study was also performed for EGFR-compound 21 complex which indicates the stability compound 21 in both ATP and allosteric site of enzyme. Further, in silico ADME prediction studies of all derivatives were found promising, signifying the drug like properties. [Display omitted] •A series of novel quinoline substituted sulphonamide (9–21) and amide (23–29) derivative has been designed, synthesised, and evaluated against the HCC827, H1975, A-549 (WT-EGFR), A-549 and BEAS-2B cell lines.•Compound 21 was found to be the most potent and exhibited promising inhibitory enzymatic activity against the EGFR L858R/T790 M (138 nM).•Docking studies revealed the binding of synthesised compounds is identical to binding patterns and interactions at the binding site of the allosteric site of EGFR-TK inhibitor's protein.•MD simulation study was performed for EGFR-compound 21 complex, indicating the stability in both ATP and allosteric site of enzyme.•Insilico ADME prediction studies of all compounds exhibited promising and signifying drug like properties.