Synthesis of Morpholine-, Piperidine-, and N-Substituted Piperazine-Coupled 2-(Benzimidazol-2-yl)-3-arylquinoxalines as Novel Potent Antitumor Agents

Abstract

A novel series of 2-(benzimidazol-2-yl)­quinoxalines with three types of pharmacophore groups, namely, piperazine, piperidine, and morpholine moieties, which are part of known antitumor drugs, was designed and synthesized. The compounds have been characterized by NMR and IR spectroscopy, high- and low-resolution mass spectrometry, and X-ray crystallography. 2-(Benzimidazol-2-yl)­quinoxalines with N-methylpiperazine substituents showed promising activity against a wide range of cancer lines, without causing hemolysis and showing little cytotoxicity against normal human Wi-38 cells (human fetal lung). A mixture of regioisomers 2-(benzimidazol-2-yl)-3-(4-fluorophenyl)-6­(and 7)-(4-methylpiperazin-1-yl)­quinoxalines (mri BIQ 13da/14da) showed a highly selective cytotoxic effect against human lung adenocarcinoma (cell line A549) with a half-maximal inhibitory concentration at the level of doxorubicin with a selectivity index of 12. The data obtained by flow cytometry, fluorescence microscopy, and multiparametric fluorescence analysis suggested that the mechanism of the cytotoxic effect of the mri BIQ 13da/14da on A549 cells may be associated with the stopping of the cell cycle in phase S and inhibition of DNA synthesis as well as with the induction of mithochondrial apoptosis. Thus, mri BIQ 13da/14da can be considered as a leading compound deserving further study, optimization, and development as a new anticancer agent.

Al2O3 promoted mechanochemical nucleophilic aromatic substitution

“…The latter is a useful intermediate for the synthesis of ferroptosis inhibitors, 51 AMP-activated protein kinase activators, 52 broblast growth factor receptor inhibitors, 53 and antitumor agents. 54,55 Substrate 12 was recovered unreacted from the milling attempt due to the high steric hindrance caused by the two methyl groups ortho to uorine.…”

Evaluation of the antimalarial activity of SAM13-2HCl with morpholine amide (SKM13 derivative) against antimalarial drug-resistant Plasmodium falciparum and Plasmodium berghei infected ICR mice

“…As a second strategy, 3 different SKM13 derivatives containing N, N -diethyl group or a ring, such as piperidine or morpholine (SAM10-2HCl, SAM12-2HCl, and SAM13-2HCl), were synthesized because piperidine or morpholine moieties can exert nontoxic antitumor activities [ 20 ]. Only SAM13-2HCl, which contained a morpholine moiety, had less cytotoxicity than SKM13-2HCl, although this was comparable with that of CQ, whereas the N, N -diethyl derivative (SAM10-2HCl) and piperidine (SAM12-2HCl) were more toxic than SKM13-2HCl.…”

Design and Synthesis of Benzenesulfonamides Coupled with Piperidine, Morpholine, and N,N‐Dimethylethanamine Moieties as Apoptotic Inducers through VEGFR2 and Topoisomerase II Inhibition

“…Secondary amines 28 and 29 were prepared similarly from direct reductive amination between the corresponding amines (11 and 19) and aldehyde 27 (Scheme 3). Target compounds (30)(31)(32)(33) were obtained from the condensation of benzenesulfonyl chlorides with amines (28 and 29) following the general procedure described in scheme 1.…”

“…The scaffold of the whole frame of the compounds maintains sulfonyl residue, which was preferred to the carbonyl group due to its ability to make multiple hydrogen bonds with protein. The piperidine, morpholine, and piperazine rings were part of the whole structure due to their distinctive structures; [32] the presence of oxygen-nitrogen atoms in morpholine structure or nitrogen-nitrogen atoms in piperazine improve the pharmacological and pharmacokinetic profiles of drug candidates containing morpholine or piperazines since the nitrogen atom sites act as hydrogen bond donors or acceptors, thus promoting the interactions with DNA as well as increasing water solubility and bioavailability [33][34][35][36][37] Accordingly, we described the discovery of new benzenesulfonamide coupled with piperidine, morpholine, and N,Ndimethylethanamine moieties through Pharmacophore hybridization as VEGFR2 and Topo II inhibitors and evaluated their ability to inhibit tumor cell growth in a selective way through apoptosis induction.…”

“…HRMS (EI): m/z [M] + (calcd. for C 29 H 36 FN 3 O 3 S: 526.24614; found: 526.25144).N-(4-fluorophenyl)-4-methoxy-N-(4-(4-methylpiperazin-1yl)benzyl)benzenesulfonamide(32). Yield 82 %; white solid; Rf = 0.55.…”