Design, Synthesis, and Biological Evaluation of 1 H -Pyrrolo[3,2- c ]quinolines as Potent and Selective Antitubulin Agents Active against Drug-Resistant Cell Lines

A library of 1H-pyrrolo[3,2-c]quinolines (PQs) was synthesized, and SAR analysis identified compounds with low-nanomolar potency in CCRF-CEM cells (IC50 = 13−18 nM) and selectivity indices > 1000-fold over BJ fibroblasts. The most active derivatives retained activity against daunorubicin-resistant and paclitaxel-resistant sublines, indicating limited cross-resistance, and compounds 4, 14, and 17 showed efflux ratios < 2 in MDR1-MDCK and Caco-2 assays. Colchicine-site engagement was supported by various assays and docking/MD simulations. ADME profiling showed high chemical and plasma stability, plasma protein binding, and moderate-to-high microsomal clearance. After i.p. dosing in CD-1 mice at 12 mg/kg, compound 17 reached a maximum plasma concentration (Cmax) of 879.9 ng/mL (2.73 μM) at tmax = 15 min, with a 103 min half-life and limited brain penetration. In zebrafish embryos, 17 induced concentration-dependent developmental abnormalities (LC50 = 198 nM at 96 hpf), consistent with antimitotic activity but pointing to a narrow therapeutic window.