Indoloquinoxaline derivatives as promising multi-functional anti-Alzheimer agents

Abstract

To confront a disease like Alzheimer’s disease having complex pathogenesis, development of multitarget-directed ligands has emerged as a promising drug discovery approach. In our endeavor towards the development of multitarget-directed ligands for Alzheimer’s disease, a series of indoloquinoxaline derivatives were designed and synthesized. In vitro cholinesterase inhibition studies revealed that all the synthesized compounds exhibited moderate to good cholinesterase inhibitory activity. 6-(6-(Piperidin-1-yl)hexyl)-6H-indolo[2,3-b]quinoxaline 9f was identified as the most potent and selective BuChE inhibitor (IC₅₀ = 0.96 µM, selectivity index = 0.17) that possessed 2 fold higher BuChE inhibitory activity compared to the commercially approved reference drug donepezil (IC₅₀ = 1.87 µM). Moreover, compound 9f is also endowed with self-induced Aβ_1-42 aggregation inhibitory activity (51.24% inhibition at 50 μM concentration). Some of the compounds of the series also displayed moderate anti-oxidant activity. To perceive a putative binding mode of the compound 9f, molecular docking studies were carried out, and the results pointed out significant interactions of compound 9f with the enzymes in the binding sites of cholinesterases as well as Aβ_1-42. Additionally, compound 9f exhibited favorable in silico ADMET properties. Put together these findings project compound 9f as a potential multitarget-directed ligand in the direction of developing novel anti-AD drugs.

Communicated by Ramaswamy H. Sarma

Keywords:

• Alzheimer’s disease
• MTDL
• cholinesterase inhibitor
• anti-Aβ aggregation
• indoloquinoxaline

Acknowledgement

The authors thank Dr. Kapil Juvale, SPPSPTM, NMIMS University, Mumbai for providing SpectramMax iD3 multi-mode microplate reader to perform Aβ_1-42 aggregation study.

Author contributions

MRY conceptualized the whole study. AMK, DVP, and NRP performed synthesis and collected data. PST and KBP contributed reagents, materials and helped in synthesis and data collection. AMK performed computational studies. KVP drafted the biological evaluation studies. AS and KBP performed the biological studies and collected data. NKP helped in synthesis and data interpretation. AMK, DVP, and NRP wrote the manuscript. MRY comprehended and approved the final version of the manuscript.

Disclosure statement

There are no conflicts of interest to disclose.

Additional information

Funding

Mange Ram Yadav acknowledges the University Grant Commission (UGC), New Delhi, for providing UGC-BSR Faculty Fellowship [No. F.18-1/2011(BSR)]. Dushyant V. Patel is thankful to the DST-INSPIRE, New Delhi for awarding Research Fellowship (IF-150660). Nirav R. Patel acknowledges the UGC, New Delhi, for awarding Senior Research Fellowship [F. No. 25-1/2014-15(BSR)/7-129/2007/(BSR)].