Development of potent cholinesterase inhibitors based on a marine pharmacophore

Elumalai, Vijayaragavan; Trobec, Tomaž; Grundner, Maja; Labriere, Christophe; Frangež, Robert; Sepčić, Kristina; Hansen, Jørn H.; Svenson, Johan

doi:10.1039/d2ob01064j

Cited by 2 publications

(4 citation statements)

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“…25 Synthetic access to potent, simplified mimics of both 1 and 3 (Figure 4) has also enabled the exploration of additional bioactivities such as cholinesterase inhibition, which is often correlated with antifouling potential. 47,48 Our studies on natural antifoulants have also probed SAR for larger molecules. Such examples include the microalgae-derived spirocyclic imine portimine (4) 27 and a series of cyclic peptides inspired by the equinatoxin II protein produced by the beadlet anemone (Actinia equine).…”

Section: ■ Structure−activity Relationshipsmentioning

confidence: 99%

“…28 Several natural compounds explored are also effective inhibitors of the cholinesterases, which may present a conserved target for biofouling inhibition. 39,44,47,48 Where specific biochemical mechanisms of action are known or posited, we employed biochemical assays from related medical or research fields. For example, we have successfully applied biomedical acetylcholinesterase 18,44 and phenoloxidase 35,62 assays to assess the antifouling potential.…”

Section: Mode Of Actionmentioning

confidence: 99%

“…In addition, the synoxazolidinones A and B ( 8 and 2 , respectively) also inhibit microalgal growth, down to 20 nM against selected strains . Synthetic access to potent, simplified mimics of both 1 and 3 (Figure ) has also enabled the exploration of additional bioactivities such as cholinesterase inhibition, which is often correlated with antifouling potential. , …”

Section: Structure–activity Relationshipsmentioning

confidence: 99%

“…Selectivity toward invertebrates for the avermectins is facilitated through motorneuron hyperpolarization via the stimulation of invertebrate-specific glutamate-gated chloride channels . Several natural compounds explored are also effective inhibitors of the cholinesterases, which may present a conserved target for biofouling inhibition. ,,, …”

Section: Mode Of Actionmentioning

confidence: 99%

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Creating New Antifoulants Using the Tools and Tactics of Medicinal Chemistry

Cahill,

Moodie,

Hertzer

et al. 2024

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS:The unwanted accumulation of marine micro-and macroorganisms such as algae and barnacles on submerged man-made structures and vessel hulls is a major challenge for any marine operation. Known as biofouling, this problem leads to reduced hydrodynamic efficiency, significantly increased fuel usage, microbially induced corrosion, and, if not managed appropriately, eventual loss of both performance and structural integrity. Ship hull biofouling in the international maritime transport network conservatively accounts for 0.6% of global carbon emissions, highlighting the global scale and the importance of this problem. Improved antifouling strategies to limit surface colonization are paramount for essential activities such as shipping, aquaculture, desalination, and the marine renewable energy sector, representing both a multibillion dollar cost and a substantial practical challenge. From an ecological perspective, biofouling is a primary contributor to the global spread of invasive marine species, which has extensive implications for the marine environment.Historically, heavy metal-based toxic biocides have been used to control biofouling. However, their unwanted collateral ecological damage on nontarget species and bioaccumulation has led to recent global bans. With expanding human activities within aquaculture and offshore energy, it is both urgent and apparent that environmentally friendly surface protection remains key for maintaining the function of both moving and stationary marine structures. Biofouling communities are typically a highly complex network of both micro-and macroorganisms, representing a broad section of life from bacteria to macrophytes and animals. Given this diversity, it is unrealistic to expect that a single antifouling "silver bullet" will prevent colonization with the exception of generally toxic biocides.For that reason, modern and future antifouling solutions are anticipated to rely on novel coating technologies and "combination therapies" where mixtures of narrow-spectrum bioactive components are used to provide coverage across fouling species. In contrast to the existing cohort of outdated, toxic antifouling strategies, such as copper-and tributyltin-releasing paints, modern drug discovery techniques are increasingly being employed for the rational design of effective yet safe alternatives. The challenge for a medicinal chemistry approach is to effectively account for the large taxonomic diversity among fouling organisms combined with a lack of welldefined conserved molecular targets within most taxa. The current Account summarizes our work employing the tools of modern medicinal chemistry to discover, modify, and develop optimized and scalable antifouling solutions based on naturally occurring antifouling and repelling compounds from both marine and terrestrial sources. Inspiration for rational design comes from targeted studies on allelopathic natural products, natural repelling peptides, and secondary metabolites from sessile marine org...

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Section: ■ Structure−activity Relationshipsmentioning

confidence: 99%

Section: Mode Of Actionmentioning

confidence: 99%

Section: Structure–activity Relationshipsmentioning

confidence: 99%

Section: Mode Of Actionmentioning

confidence: 99%

See 2 more Smart Citations

Creating New Antifoulants Using the Tools and Tactics of Medicinal Chemistry

Cahill,

Moodie,

Hertzer

et al. 2024

Acc. Chem. Res.

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Advances in Cholinesterase Inhibitor Research—An Overview of Preclinical Studies of Selected Organoruthenium(II) Complexes

Žužek

2024

IJMS

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Cholinesterase (ChE) inhibitors are crucial therapeutic agents for the symptomatic treatment of certain chronic neurodegenerative diseases linked to functional disorders of the cholinergic system. Significant research efforts have been made to develop novel derivatives of classical ChE inhibitors and ChE inhibitors with novel scaffolds. Over the past decade, ruthenium complexes have emerged as promising novel therapeutic alternatives for the treatment of neurodegenerative diseases. Our research group has investigated a number of newly synthesized organoruthenium(II) complexes for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Three complexes (C1a, C1-C, and C1) inhibit ChE in a pharmacologically relevant range. C1a reversibly inhibits AChE and BChE without undesirable peripheral effects, making it a promising candidate for the treatment of Alzheimer’s disease. C1-Cl complex reversibly and competitively inhibits ChEs, particularly AChE. It inhibits nerve-evoked skeletal muscle twitch and tetanic contraction in a concentration-dependent manner with no effect on directly elicited twitch and tetanic contraction and is promising for further preclinical studies as a competitive neuromuscular blocking agent. C1 is a selective, competitive, and reversible inhibitor of BChE that inhibits horse serum BChE (hsBChE) without significant effect on the peripheral neuromuscular system and is a highly species-specific inhibitor of hsBChE that could serve as a species-specific drug target. This research contributes to the expanding knowledge of ChE inhibitors based on ruthenium complexes and highlights their potential as promising therapeutic candidates for chronic neurodegenerative diseases.

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Development of potent cholinesterase inhibitors based on a marine pharmacophore

Abstract: The management of neurological disorders such as dementia associated with Alzheimer’s or Parkinson’s disease includes the use of cholinesterase inhibitors. These compounds can slow down the progression of these diseases...

Cited by 2 publications

References 64 publications

Creating New Antifoulants Using the Tools and Tactics of Medicinal Chemistry

Creating New Antifoulants Using the Tools and Tactics of Medicinal Chemistry

Advances in Cholinesterase Inhibitor Research—An Overview of Preclinical Studies of Selected Organoruthenium(II) Complexes

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