Novel benzoic acid derivatives: Synthesis and biological evaluation as multitarget acetylcholinesterase and carbonic anhydrase inhibitors

Topic: Brain proteins, microglia and lab models

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia, memory impairment, cognitive dysfunction, and speech impairment. The utility of cholinergic replacement by acetylcholinesterase (AChE) inhibitors in AD treatment has been well documented so far. Recently, studies have also evidenced that human carbonic anhydrases (hCAs) serve as an important target for AD treatment. In this direction, the improvement of new multitarget drugs, which can simultaneously modulate several mechanisms or targets included in the AD pathway, may be a potent strategy to treat AD. In light of these data for understanding and developing AD-related multitarget AChE and hCAs inhibitors, in this study, novel methylene-aminobenzoic acid and tetrahydroisoquinolynyl-benzoic acid derivatives (4a-g and 6a-g) were designed. The synthesized analogs were experimentally validated for their effects by in vitro and direct enzymatic tests. Also, the compounds were subjected to in silico monitoring with Schrödinger Suite software to assign binding affinities of potential derivatives based on Glide XP scoring, molecular mechanics-generalized Born surface area computing, and validation by molecular docking. The results revealed that 6c (1,3-dimethyldihydropyrimidine-2,4-(1H,3H)-dione-substituted, K I value of 33.00 ± 0.29 nM), 6e (cyclohexanone-substituted, K I value of 18.78 ± 0.09 nM), and 6f (2,2-dimethyl-1,3-dioxan-4-one-substituted, K I value of 13.62 ± 0.21 nM) from the benzoic acid derivatives in this series were the most promising derivatives, as they exhibited a good multifunctional inhibition at all experimental levels and in the in silico validation against hCA I, hCA II, and AChE, respectively, for the treatment of AD.

Key findings

• The results revealed that 6c (1,3-dimethyldihydropyrimidine-2,4-(1H,3H)-dione-substituted, K I value of 33.00 ± 0.29 nM), 6e (cyclohexanone-substituted, K I value of 18.78 ± 0.09 nM), and 6f (2,2-dimethyl-1,3-dioxan-4-one-substituted, K I value of 13.62 ± 0.21 nM) from the benzoic acid derivatives in this series were the most promising derivatives, as they exhibited a good multifunctional inhibition at all experimental levels and in the in silico validation against hCA I, hCA II, and AChE, respectively, for the treatment of AD.

Why it matters

This laboratory study designed and tested new benzoic acid derivatives that inhibit acetylcholinesterase and carbonic anhydrase in vitro, with some compounds showing low KI values. These are early in-vitro and in-silico findings and do not establish any treatment, cure, or prevention for Alzheimer's disease in people.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1002/ardp.202000282
• PubMed: 33155700
• Original source →

May need a subscription OpenAlex found no free copy of the full text (checked 6 Feb 1020), so the publisher may charge for it. The PubMed abstract is free.

@article{kalayc2021-33155700,
  author  = {Kalaycı, M. and Türkeş, C. and Arslan, M. and Demir, Y. and Ş, Beydemir},
  title   = {{Novel benzoic acid derivatives: Synthesis and biological evaluation as multitarget acetylcholinesterase and carbonic anhydrase inhibitors}},
  journal = {Archiv der Pharmazie},
  year    = {2021},
  doi     = {10.1002/ardp.202000282},
  pmid    = {33155700},
  url     = {https://doi.org/10.1002/ardp.202000282}
}

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