Synthesis of novel 4,5‐dihydropyrrolo[1,2‐a]quinoxalines, pyrrolo[1,2‐a]quinoxalin]‐2‐ones and their antituberculosis and anticancer activity

Abstract

A facile strategy was developed for the synthesis of biologically important 4,5dihydropyrrolo[1,2-a]quinoxalines and pyrrolo[1,2-a]quinoxalin]-2-ones by treating 2-(1H-pyrrol-1-yl)anilines with imidazo[1,2-a]pyridine-3-carbaldehyde or isatin, using amidosulfonic acid (NH 3 SO 3) as a solid catalyst in water at room temperature. The protocol has been extended to electrophile ninhydrin. The catalyst could be recycled for six times without the loss of activity. The compounds were evaluated for their antituberculosis, antibacterial, and anticancer activities. It is worth noting that compounds 3d and 3e demonstrated a minimum inhibitory concentration value of 6.25 µM against Mycobacterium tuberculosis H37Rv, whereas compounds 3d, 3g, 5d, 5e, and 5i showed a remarkable inhibition of A549, DU145, HeLa, HepG2, MCF-7, and B16-F10 cell lines, respectively. Staphylococcus aureus was inhibited by compounds 5b, 5e, 5d, 5g, and 5l at 32 µg/ml. K E Y W O R D S 4,5-dihydropyrrolo[1,2-a]quinoxalines, antituberculosis agents, pyrrolo[1,2-a]quinoxalin-2-ones, reusable catalyst 1 | INTRODUCTION Quinoxalines are nitrogen-containing heterocyclic compounds [1] exhibiting various biological activities, [2] acting as glucagon receptor antagonist, [3] inhibitors of human protein kinase CK2, [4] 5-HT 3 receptor agonist, [5] and gamma-aminobutyric acid receptor agonist. [6] Among these quinoxalines (Figure 1), 4,5-dihydropyrrolo[1,2-a]quinoxaline (1) is a key pharmacologically privileged scaffold exhibiting various activities including polycystic kidney disease inhibition. [7] The pyrrolo[1,2-a]quinoxaline derivative 2 showed an antipsychotic activity, [8] whereas 3 was found to be an adenosine A3 receptor modulator. [9] The pyrrolo[1,2-a]quinoxaline 4 has shown anti-HIV potential, [10] whereas 5 has been reported for its antiproliferative activity. [11] There are few reports on the synthesis of 4,5-dihydropyrrolo[1,2-a] quinoxalines and their spiro derivatives. [12] Preetham and Nath [13] reported the synthesis of pyrrolo-[1,2-a]quinoxalines and spiro derivatives using 2-(1H-pyrrol-1-yl)aniline with aldehyde or isatin or ketone in the presence of p-dodecylbenzenesulfonic acid catalyst in ethanol. Verma et al. [14] used 10 mol% AlCl 3 in tetrahydrofuran for the same transformation. In contrast, Zhou et al. [15] synthesized 12b-methyl-1,12bdihydrodipyrrolo[1,2-a:2′,1′-c]quinoxalin-3(2H)-one from 2-(1H-pyrrol-1yl)aniline and 4-pentynoic acid in the presence of Au(I) catalyst in water at 100°C. 14 Water Amidosulfonic acid 3 98 15 Water Amidosulfonic acid 4 98 Note: Reagents and conditions: 1a (0.088 mmol), 2a (0.088 mmol, 25 mg) in 2.0 ml of solvent at room temperature. Isolated yields (without column chromatography).

Quinoxaline Moiety: A Potential Scaffold against Mycobacterium tuberculosis

“…In addition, several novel 4,5-dihydropyrrolo[1,2- a ]quinoxalines and pyrrolo[1,2- a ]quinoxaline-2-ones were synthesized from the reaction between 2-(1 H -pyrrol-1-yl)anilines and imidazo[1,2- a ]pyridine-3-carbaldehyde or isatin and are of current interest as antimycobacterial agents [ 35 ] ( Figure 5 ).…”

“…Five 4-substitued 4,5-dihydropyrrolo[1,2- a ]quinoxalines and only one pyrrolo[1,2- a ]quinoxaline-2-one derivative displayed potent antimycobacterial activity, with MIC ranging from 6.25 to 12.5 µg/mL. However, no clear structure–activity relationship could be demonstrated from the small number of synthesized compounds [ 35 ].…”

Synthesis, Crystal Structure and Anti-Leukemic Activity of 1,3-Dihydro-1-{1-[4-(4-phenylpyrrolo[1,2-a]quinoxalin-3-yl)benzyl]piperidin-4-yl}-2H-benzimidazol-2-one

“…219-221 • C; IR (KBr) 1695 (CO), 1602 (C=N). 1 H-NMR (δ, ppm, CDCl 3 , 300 MHz): 9.92 (s, 1H, HC=O), 8.12 (d, 1H, J = 2.85 Hz, H-1 ), 8.10 (dd, 1H, J = 8.10 and 1.50 Hz, H-9 ), 7.97 (dd, 1H, J = 8.10 and 1.50 Hz, H-6 ), 7.60 (ddd, 1H, J = 8.10, 7.85 and 1.50 Hz, H-8 ), 7.53 (ddd, 1H, J = 8.10, 7.85 and 1.50 Hz, H-7 ), 7…”

“…Among them, the pyrrolo[1,2-a]quinoxalines were common motifs, with a broad range of pharmacological properties, and could be considered as a privileged substructure for drug design [1,2]. Such nitrogen-containing valuable heterocyclic compounds have been previously described as antipsychotic agents [3], antiviral agents [4], adenosine receptor modulators [5], antituberculosis agents [6,7], antiprotozoal agents [8][9][10][11][12][13][14] and anticancer agents [15][16][17][18][19]. The discovery of novel and original anti-cancer derivatives is one of the most important goals in pharmaceutical chemistry.…”

In vivo‐ and in silico‐driven identification of novel synthetic quinoxalines as anticonvulsants and AMPA inhibitors

“…In addition, the improvement of γ-aminobutyric acid (GABA)-mediated synaptic transmission in the cerebellum by both compounds has also been proved. [17] Additionally, quinoxaline derivatives were recently reported to possess a diverse pharmacological activity, especially antitubercular [23] and anticancer. [24] However, the pentylenetetrazol (PTZ)-induced convulsion model was used to evaluate the antiepileptic properties of triazolylchroman 4.…”