Imidazo[1,2-a]quinoxalines Derivatives Grafted with Amino Acids: Synthesis and Evaluation on A375 Melanoma Cells

Abstract

Imiqualines (imidazoquinoxaline derivatives) are anticancer compounds with high cytotoxic activities on melanoma cell lines. The first generation of imiqualines, with two lead compounds (EAPB0203 and EAPB0503), shows remarkable in vitro (IC50 = 1 570 nM and IC50 = 200 nM, respectively, on the A375 melanoma cell line) and in vivo activity on melanoma xenografts. The second generation derivatives, EAPB02302 and EAPB02303, are more active, with IC50 = 60 nM and IC50 = 10 nM, respectively, on A375 melanoma cell line. The aim of this study was to optimize the bioavailability of imiqualine derivatives, without losing their intrinsic activity. For that, we achieved chemical modulation on the second generation of imiqualines by conjugating amino acids on position 4. A new series of twenty-five compounds was efficiently synthesized by using microwave assistance and tested for its activity on the A375 cell line. In the new series, compounds 11a, 9d and 11b show cytotoxic activities less than second generation compounds, but similar to that of the first generation ones (IC50 = 403 nM, IC50 = 128 nM and IC50 = 584 nM, respectively). The presence of an amino acid leads to significant enhancement of the water solubility for improved drugability.

Imidazoquinoxaline as a Privileged Fused Pharmacophore in Anticancer Drug Development: A Review of Synthetic Strategies and Medicinal Aspects

“…Chouchou et al designed and synthesized a series of 25 new imidazoquinoxaline derivatives from which compounds 18 a-f, 19 a-h, 20 b-d, and 21 a-h were tested for their in vitro anti-proliferative activity on human melanoma cell line A375. [49] The main objective was to design imidazoquinoxaline deriva-tives with improved bioavailability without loss of intrinsic activity. For this purpose, the imidazoquinoxaline moiety was conjugated with various amino acids at C4.…”

Design and Synthesis of Non-Covalent Imidazo[1,2-a]quinoxaline-Based Inhibitors of EGFR and Their Anti-Cancer Assessment

“…Overall, binding pattern and docking score of the designed compound was better than I and II (See Supplementary Materials, Figure S1, Table S1). Furthermore, imidazole-fused [11,18] quinoxaline [19], in particular, imidazo[1,2-a]quinoxalines have gained significant interest due to their broad-spectrum activities [20,21], including IκB kinase (IKK) [22] and lymphocyte-specific protein tyrosine kinase (LCK) [23] inhibitory activities. In the recent past, we were interested in developing the synthetic approaches and assessing the biological activities of pyrazolo[1,5-c]quinazolines [12][13][14][15], which eventually emerged as active EGFR inhibitors [16,17].…”

“…Overall, binding pattern and docking score of the designed compound was better than I and II (See Supplementary Materials, Figure S1, Table S1 ). Furthermore, imidazole-fused [ 11 , 18 ] quinoxaline [ 19 ], in particular, imidazo[1,2- a ]quinoxalines have gained significant interest due to their broad-spectrum activities [ 20 , 21 ], including IκB kinase (IKK) [ 22 ] and lymphocyte-specific protein tyrosine kinase (LCK) [ 23 ] inhibitory activities.…”

Facile synthesis of C6‐substituted benz[4,5]imidazo[1,2‐a]quinoxaline derivatives and their anticancer evaluation

“…[ 16 ] Chemical modifications of 4 led to EAPB02303 ( 5 ), which showed excellent anticancer activity (IC 50 = 10 nM) against A375 cells. [ 17 ] In addition, EAPB0503 ( 6 ), an analog of EAPB0203, demonstrated excellent cell growth inhibition on human chronic myeloid leukemia (CML) cell lines. Most important, EAPB0503 inhibited the proliferation of imatinib‐resistant CML cells, offering promising therapeutic modalities.…”