2. Academic Validation
  3. Multitarget action of Benzothiazole-piperazine small hybrid molecule against Alzheimer's disease: In silico, In vitro, and In vivo investigation

Multitarget action of Benzothiazole-piperazine small hybrid molecule against Alzheimer's disease: In silico, In vitro, and In vivo investigation

  • Biomed Pharmacother. 2024 Apr 1:174:116484. doi: 10.1016/j.biopha.2024.116484.
Chandra Bhushan Mishra 1,  Shruti Shalini 2,  Siddharth Gusain 2,  Pawan Kumar 3,  Shikha Kumari 4,  Yong-Sung Choi 5,  Jyoti Kumari 2,  Bala Krishna Moku 6,  Anita Kumari Yadav 2,  Amresh Prakash 7,  Raok Jeon 8,  Manisha Tiwari 9
Affiliations

Affiliations

  • 1 College of Pharmacy, Sookmyung Women's University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, South Korea; Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: chandra.medicinalchemist@gmail.com.
  • 2 Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India.
  • 3 School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
  • 4 Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
  • 5 College of Pharmacy, Sookmyung Women's University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, South Korea.
  • 6 Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 7 Amity Institute of Integrative Sciences and Health (AIISH), Amity University Haryana, Amity Education Valley, Gurgaon 122413, India.
  • 8 College of Pharmacy, Sookmyung Women's University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, South Korea. Electronic address: rjeon@sookmyung.ac.kr.
  • 9 Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India. Electronic address: mtiwari07@gmail.com.
PMID: 38565058 DOI: 10.1016/j.biopha.2024.116484
Abstract

A novel small molecule based on benzothiazole-piperazine has been identified as an effective multi-target-directed ligand (MTDL) against Alzheimer's disease (AD). Employing a medicinal chemistry approach, combined with molecular docking, MD simulation, and binding free energy estimation, compound 1 emerged as a potent MTDL against AD. Notably, compound 1 demonstrated efficient binding to both AChE and Aβ1-42, involving crucial molecular interactions within their active sites. It displayed a binding free energy (ΔGbind) -18.64± 0.16 and -16.10 ± 0.18 kcal/mol against AChE and Aβ1-42, respectively. In-silico findings were substantiated through rigorous in vitro and in vivo studies. In vitro analysis confirmed compound 1 (IC50=0.42 μM) as an effective, mixed-type, and selective AChE Inhibitor, binding at both the enzyme's catalytic and peripheral anionic sites. Furthermore, compound 1 demonstrated a remarkable ability to reduce the aggregation propensity of Aβ, as evidenced by Confocal laser scanning microscopy and TEM studies. Remarkably, in vivo studies exhibited the promising therapeutic potential of compound 1. In a scopolamine-induced memory deficit mouse model of AD, compound 1 showed significantly improved spatial memory and cognition. These findings collectively underscore the potential of compound 1 as a promising therapeutic candidate for the treatment of AD.

Keywords

Alzheimer's disease; Benzothiazole; Dementia; In silico; MD simulation; Multitarget.

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