Synthesis of N-Alkyl-3-[2-oxoquinolin-1(2 H)-yl]propanoic Acid Derivatives and Related Compounds: Cytotoxicity and EGFR Inhibition of Some Propanamide Derivatives

Abstract

A series of 20 new structure-modified quinolin-2-one derivatives were prepared for biological evaluation. This was successfully achieved based on chemoselective reactions of heterocyclic amides with acrylic acid derivatives, which gave 3-[2-oxoquinolin-1-(2H)-yl] propanoic acid derivatives (N-substitution via a unique behavior). The ester was reacted with hydrazine to afford the corresponding hydrazide. Both the corresponding ester and hydrazide were used as building blocks to modify the quinolone structure and give N-hydroxyl propanamides, oxadiazoles, and thiosemicarbazides. The corresponding carboxylic acid and hydrazide were used to prepare several amides: N-alkyl-3-[2-oxoquinolin-1(2H)-yl]propanamides via azide and dicyclohexyl carbodiimide coupling methods. Among derivatives, compound 9e exhibited potent cytotoxicity against MCF-7 cells with an IC₅₀ value of 1.32 μM compared to doxorubicin with an IC₅₀ value of 1.21 μM. Additionally, it caused potent EGFR inhibition by 97% with an IC₅₀ value of 16.89 nM compared to Erlotinib with an IC₅₀ value of 29.8 nM. Finally, the binding mode of compound interactions toward EGFR was highlighted using a molecular docking study; compound 9e exhibited good binding affinity with a binding energy of -17.89 kcal/mol, and it formed H-bond interactions with Met 769 as the key amino acid of interaction. Accordingly, compound 9e may be developed as an EGFR-oriented chemotherapeutic antibreast cancer agent.

Figure 1

(A) Some quinoline-based anticancer drugs are kinase inhibitors. (B) Design strategy for the synthesized compounds.

Scheme 1. Preparation of 3-[2-Oxoquinolin-1-(2H)-yl]propanoic Acid Derivatives 2a–c

Scheme 2. Chemistry of Methyl 3-[2-Oxoquinolin-1(2H)-yl]propanoate (2a) and 3-[2-Oxoquinolin-1(2H)-yl]propanhydrazide (3)

Scheme 3. Preparation of N-Alkyl-3-[2-oxoquinolin-1(2H)-yl]propanamides 9a–j

Figure 2

Selected signals for the ¹H and ¹³C NMR spectra of 1-[2-(1,3,4-oxadiazol-2-yl)ethyl]quinolin-2(1H)-one (6), 4-(4-methoxyphenyl)-1-{3-[2-oxoquinolin-1(2H)-yl]propanoyl}thiosemicarbazide (8c), and N-isopropyl-3-[2-oxoquinolin-1(2H)-yl]propanamide (9c).

Figure 3

Cell growth inhibition versus log concentrations of compounds 9c, 9d, 9e, and 9g cells using the MTT assay. Values are expressed as mean ± SD of three independent values.

Figure 4

Binding mode and ligand–receptor interactions of the cocrystallized ligand (cyan-colored) and compound 9e (yellow-colored) inside the receptor binding site of EGFR protein.