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Small synthetic mimics of cationic antimicrobial peptides represent a promising class of compounds with leads in clinical development for the treatment of persistent microbial infections. The activity and selectivity of these compounds rely on a balance between hydrophobic and cationic components, and here, we explore the activity of 19 linear cationic tripeptides against five different pathogenic bacteria and fungi, including clinical isolates. The compounds incorporated modified hydrophobic amino acids inspired by motifs often found in bioactive marine secondary metabolites in combination with different cationic residues to probe the possibility of generating active compounds with improved safety profiles. Several of the compounds displayed high activity (low mu M concentrations), comparable with the positive controls AMC-109, amoxicillin, and amphotericin B. A higher activity was observed against the fungal strains, and a low in vitro off-target toxicity was observed against erythrocytes and HeLa cells, thereby illustrating effective means for tuning the activity and selectivity of short antimicrobial peptides.

Marine biofouling plagues all maritime industries at vast economic and environmental cost. Previous and most current methods to control biofouling have employed highly persistent toxins and heavy metals, including tin, copper, and zinc. These toxic methods are resulting in unacceptable environmental harm and are coming under immense regulatory pressure. Eco-friendly alternatives are urgently required to effectively mitigate the negative consequence of biofouling without causing collateral harm. Amphiphilic micropeptides have recently been shown to exhibit excellent broad-spectrum antifouling activity, with a non-toxic mode of action and innate biodegradability. The present work focused on incorporating the pharmacophore derived from amphiphilic micropeptides into a 2,5-diketopiperazine (DKP) scaffold. This privileged structure is present in a vast number of natural products, including marine natural product antifoulants, and provides advantages of synthetic accessibility and adaptability. A novel route to symmetrical tetrasubstituted DKPs was developed and a library of amphiphilic 2,5-DKPs were subsequently synthesised. These biodegradable compounds were demonstrated to be potent marine antifoulants displaying broad-spectrum activity in the low micromolar range against a range of common marine fouling organisms. The outcome of planned coating and field trials will dictate the future development of the lead compounds.

Stationary and slow-moving marine organisms regularly employ a natural product chemical defense to prevent being colonized by marine micro- and macroorganisms. While these natural antifoulants can be structurally diverse, they often display highly conserved chemistries and physicochemical properties, suggesting a natural marine antifouling pharmacophore. In our current report, we investigate the marine natural product phidianidine A, which displays several chemical properties found in highly potent marine antifoulants. Phidianidine A and synthetic analogues were screened against the settlement and metamorphosis of Amphibalanus improvisus cyprids, and several of the compounds displayed inhibitory activities at low micromolar concentrations with IC50 values down to 0.7 μg/mL observed. The settlement study highlights that phidianidine A is a potent natural antifoulant and that the scaffold can be tuned to generate simpler and improved synthetic analogues. The bioactivity is closely linked to the size of the compound and to its basicity. The study also illustrates that active analogues can be prepared in the absence of the natural constrained 1,2,4-oxadiazole ring. A synthetic lead analogue of phidianidine A was incorporated in a coating and included in antifouling field trials, where it was shown that the coating induced potent inhibition of marine bacteria and microalgae settlement.

Inhibition of cholinesterases is a common approach for the management of several disease states. Most notably, cholinesterase inhibitors are used to alleviate the symptoms of neurological disorders like dementia and Alzheimer's disease and treat myasthenia gravis and glaucoma. Historically, most drugs of natural origin have been isolated from terrestrial sources and inhibitors of cholinesterases are no exception. However, the last 50 years have seen a rise in the quantity of marine natural products with close to 25 000 reported in the scientific literature. A number of marine natural products with potent cholinesterase inhibitory properties have also been reported; isolated from a variety of marine sources from algae to ascidians. Representing a diverse range of structural classes, these compounds provide inspirational leads that could aid the development of therapeutics. The current paper aims to, for the first time, comprehensively summarize the literature pertaining to cholinesterase inhibitors derived from marine sources, including the first papers published in 1974 up to 2018. The review does not report bioactive extracts, only isolated compounds, and a specific focus lies on compounds with reported doseresponse data. In vivo and mechanistic data is included for compounds where this is reported. In total 185 marine cholinesterase inhibitors and selected analogs have been identified and reported and some of the compounds display inhibitory activities comparable or superior to cholinesterase inhibitors in clinical use.

The marine environment remains a rich source for the discovery and development of novel bioactive compounds. The present paper describes the design, synthesis and biological evaluation of a library of small molecule heterocyclic mimetics of the marine 2,5-diketopiperazine barettin which is a powerful natural antioxidant. By mainly focusing on the influence from the brominated indole and heterocyclic core of barettin, a library of 19 compounds was prepared. The compounds comprised a heterocyclic core, either a 2,5 diketopiperazine, an imidazolidinedione or a thioxothiazolidinone, which were mainly monosubstituted with ranging bulky substituents. The prepared compounds were screened for activity in a cellular lipid peroxidation assay using HepG2 cells. Several of the synthetic compounds showed antioxidant properties superior to the positive control barettin. Two of the prepared compounds displayed inhibitory activity similar to commercial antioxidants with significant inhibition at low mu g/mL concentrations. The toxicity of the compounds was also investigated against MRC-5 lung fibroblasts and none of the included compounds displayed any toxicity at 50 mu g/mL.

Both pathogenic bacteria and fungi are developing resistance to common antimicrobial treatment at an alarming rate. To counteract this development, it is of essence to develop new classes of antimicrobial agents. One such class is antimicrobial peptides, most of which are derived from the innate immune system. In this study, a series of novel 2,5-diketopiperazines were designed, synthesized, and evaluated for their antimicrobial abilities. The compounds were designed to probe the pharmacophore dictated for short linear mimics of antimicrobial cationic peptides, and as such, the compounds contain a range of cationic and hydrophobic functionalities. Several of the prepared compounds displayed high antimicrobial activities toward bacteria and also against human pathogenic fungi. Of particular interest was the high activity toward fungal strains with an inherent increased resistance toward conventional antifungal agents. The most effective compounds displayed inhibition of Candida glabrata and Candida krusei growth at concentrations between 4 and 8 mu g/mL, which is comparable to commercial antifungal agents in use. Structure activity relationship studies revealed a similar dependence on cationic charge and the volume of the hydrophobic bulk as for linear cationic antimicrobial peptides. Finally, the hemolytic activity of selected compounds was evaluated, which revealed a potential to produce active compounds with attenuation of unwanted hemolysis. The findings highlight the potential of cyclic cationic amphiphilic peptidomimetics as a class of promising compounds for the treatment of infections caused by microorganisms with an increased resistance to conventional antimicrobial agents.

The current study represents the first comprehensive investigation into the general antifouling activities of the natural drimane sesquiterpene polygodial. Previous studies have highlighted a high antifouling effect toward macrofoulers, such as ascidians, tubeworms, and mussels, but no reports about the general antifouling effect of polygodial have been communicated before. To probe the structural and chemical basis for antifouling activity, a library of 11 polygodial analogues was prepared by semisynthesis. The library was designed to yield derivatives with ranging polarities and the ability to engage in both covalent and noncovalent interactions, while still remaining within the drimane sesquiterpene scaffold. The prepared compounds were screened against 14 relevant marine micro- and macrofouling species. Several of the polygodial analogues displayed inhibitory activities at sub-microgram/mL concentrations. These antifouling effects were most pronounced against the macrofouling ascidian Ciona savignyi and the barnacle Balanus improvisus, with inhibitory activities observed for selected compounds comparable or superior to several commercial antifouling products. The inhibitory activity against the microfouling bacteria and microalgae was reversible and significantly less pronounced than for the macrofoulers. This study illustrates that the macro- and microfoulers are targeted by the compounds via different mechanisms.

The current study reports the first comprehensive evaluation of a class of allelopathic terrestrial natural products as antifoulants in a marine setting. To investigate the antifouling potential of the natural dihydrostilbene scaffold, a library of 22 synthetic dihydrostilbenes with varying substitution patterns, many of which occur naturally in terrestrial plants, were prepared and assessed for their antifouling capacity. The compounds were evaluated in an extensive screen against 16 fouling marine organisms. The dihydrostilbene scaffold was shown to possess powerful general antifouling effects against both marine microfoulers and macrofoulers with inhibitory activities at low concentrations. The species of microalgae examined displayed a particular sensitivity toward the evaluated compounds at low ng/mL concentrations. It was shown that several of the natural and synthetic compounds exerted their repelling activities via nontoxic and reversible mechanisms. The activities of the most active compounds such as 3,5-dimethoxybibenzyl (5), 3,4-dimethoxybibenzyl (9), and 3-hyolroxy-3',4,5'-trirnethoxybibenzyl (20) were comparable to the commercial antifouling booster biocide. Sea-nine, which was employed as a positive control. The investigation of terrestrial allelopathic natural products to counter marine fouling represents a novel strategy for the design of "green" antifouling technologies, and these compounds offer a potential alternative to traditional biocidal antifoulants.