[1,2,4]triazolo[4,3-a]quinoxaline as Novel Scaffold in the Imiqualines Family: Candidates with Cytotoxic Activities on Melanoma Cell Lines

Abstract

Cutaneous melanoma is one of the most aggressive human cancers and is the deadliest form of skin cancer, essentially due to metastases. Novel therapies are always required, since cutaneous melanoma develop resistance to oncogenic pathway inhibition treatment. The Imiqualine family is composed of heterocycles diversely substituted around imidazo[1,2-a]quinoxaline, imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline, and pyrazolo[1,5-a]quinoxaline scaffolds, which display interesting activities on a panel of cancer cell lines, especially melanoma cell lines. We have designed and prepared novel compounds based on the [1,2,4]triazolo[4,3-a]quinoxaline scaffold through a common synthetic route, using 1-chloro-2-hydrazinoquinoxaline and an appropriate aldehyde. Cyclization is ensured by an oxidation-reduction mechanism using chloranil. The substituents on positions 1 and 8 were chosen based on previous structure–activity relationship (SAR) studies conducted within our heterocyclic Imiqualine family. Physicochemical parameters of all compounds have also been predicted. A375 melanoma cell line viability has been evaluated for 16 compounds. Among them, three novel [1,2,4]triazolo[4,3-a]quinoxalines display cytotoxic activities. Compounds 16a and 16b demonstrate relative activities in the micromolar range (respectively, 3158 nM and 3527 nM). Compound 17a shows the best EC50 of the novel series (365 nM), even if EAPB02303 remains the lead of the entire Imiqualine family (3 nM).

Chemistry, Synthesis, and Structure Activity Relationship of Anticancer Quinoxalines

“…Figure 9 shows the molecular structures of compound 14 and its SAR [96]. Yuan and coworkers (2019) prepared two forms of naphthyl quinoxaline thymidine conjugates cis (15) and trans (16) as a novel class of cytotoxic molecules that efficiently induced in vivo antitumor activity through the vaccination application. The two conjugates 15 and 16 exhibited a pronounced cytotoxicity post 400 nm UVA activation at 3 mW/cm 2 for 20 min with the IC50 = 44.3 and 26.6 nM, respectively.…”

“…The two conjugates 15 and 16 exhibited a pronounced cytotoxicity post 400 nm UVA activation at 3 mW/cm 2 for 20 min with the IC50 = 44.3 and 26.6 nM, respectively. This study connected the immunological effects and the antitumor activity of quinoxaline derivatives through Yuan and coworkers (2019) prepared two forms of naphthyl quinoxaline thymidine conjugates cis (15) and trans (16) as a novel class of cytotoxic molecules that efficiently induced in vivo antitumor activity through the vaccination application. The two conjugates 15 and 16 exhibited a pronounced cytotoxicity post 400 nm UVA activation at 3 mW/cm 2 for 20 min with the IC 50 = 44.3 and 26.6 nM, respectively.…”

“…It is a low-melting solid (29-30 • C), soluble in water, and a weak base (pKa = 0.56) [15]. Several studies were performed and displayed a wide range of pharmacological activities for quinoxaline derivatives (Figure 1) [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Additionally, quinoxalines are used for crop protection as a component of insecticides, herbicides, and fungicides [31][32][33][34][35].…”

Sequential, Electrochemical‐Photochemical Synthesis of 1,2,4‐Triazolo‐[4,3‐a]pyrazines

“…Cyclization of 2 is then commonly performed using orthoesters to form the 1,2,4-triazolo-[4,3a]pyrazine (3) (Scheme 1a). [8][9][10][11][12]14,25,26] Recently, Maji et al, published on the regioselective synthesis of,1,2,4-triazoles and 1,2,4-triazolo-[4,3-a]pyrazines using an o-quino-enzyme to catalyze the cyclization of hydrazine substituted heterocycles with primary amines in the presence of FeCl 3 as a Lewis acid cocatalyst and O 2 as an oxidant. [27] Although effective, these procedures require hydrazine, as well as a chlorinated starting material to obtain the desired heterocyclic starting material.…”