Dual-target pyrrolo[1,2-a]quinoxaline hydrazones : bridging anti-leukemic and antimalarial drug discovery

This study reports the synthesis, structural characterization and evaluation of new pyrrolo[1,2-a]quinoxaline-2-carboxylic acid hydrazone derivatives (1a–1f) as structural analogues of the antileukemic reference compounds HY-143278 and NVX-412, and synthesized from 2-nitroaniline through a six-step pathway. Structural characterization was achieved by ¹H/¹³C NMR, HRMS, and single-crystal X-ray diffraction (for 1c, 1d, and 1f), confirming the (E)-configuration of the hydrazone linkage and, for 1d, a minor ketoenol tautomeric equilibrium in solution.

These compounds were first evaluated in vitro against the human acute myeloid leukemia cell line MV4-11 (FLT3-ITD mutated). Only the pyridin-2-yl derivative 1a showed measurable antiproliferative activity (IC₅₀ = 15.51 µM), with low toxicity toward healthy hFF-1 fibroblasts (selectivity index > 3.22). Given the structural similarity between hydrazones 1and a recently reported antimalarial quinoline-hydrazone, the series was further screened for antiplasmodial activity against the chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of Plasmodium falciparum. The pyridin-4-yl derivative 1c displayed the highest potency against 3D7 (IC₅₀ = 0.02 µM, SI > 5000), while the pyrimidinyl derivative 1e was the most active against W2 (IC₅₀ = 0.03 µM, SI > 3333) both markedly outperforming chloroquine's selectivity profile. None of the compounds showed cytotoxicity toward human HepG2 hepatic cells (CC₅₀ > 100 µM), and the ferrocenyl analogue 1f was unexpectedly inactive against both parasitic strains.

Overall, these results demonstrate that subtle structural modifications of the pyrrolo[1,2-a]quinoxaline-hydrazone scaffold drive distinct and selective biological profiles, positioning this chemical series as a versatile platform bridging anti-leukemic and antimalarial drug discovery.