Antifungal activity of sustainable histone deacetylase inhibitors against planktonic cells and biofilms of Candida spp. and Cryptococcusneoformans.

The limited therapeutic options for fungal infections and the increased incidence of fungal strains resistant to antifungal drugs, especially Candida spp., require the development of new antifungal drugs and strategies. Histone deacetylase inhibitors (HDACi), like vorinostat, have been studied in cancer treatment and have antifungal effects, acting alone or synergistically with classical antifungals. Here we investigated the antifungal activity of two novel sustainable HDACi (LDT compounds) based on vorinostat structure. Molecular docking simulation studies reveal that LDT compounds can bind to Class-I HDACs of Candida albicans, C. tropicalis, and Cryptococcus neoformans, which showed similar binding mode to vorinostat. LDT compounds showed moderate activity when tested alone against fungi but act synergistically with antifungal azoles against Candida spp. They reduced biofilm formation by more than 50% in C. albicans (4 µg/mL), with the main action in fungal filamentation. Cytotoxicity of the LDT compounds against RAW264.7 cells was evaluated and LDT536 demonstrated cytotoxicity only at the concentration of 200 µmol/L, while LDT537 showed IC50 values of 29.12 µmol/L. Our data indicated that these sustainable and inexpensive HDACi have potential antifungal and antibiofilm activities, with better results than vorinostat, although further studies are necessary to better understand the mechanism against fungal cells.

Fungal infections are neglected diseases that affect more than a billion people worldwide. Some histone deacetylase inhibitors can act against fungal cells. Our data reveal that HDACi LDT536 and LDT537 have potential antibiofilm and antifungal activities.

Sustainable multifunctional phenolic lipids as potential therapeutics in Dentistry.

Phenolic lipids components of the cashew nutshell liquid (CNSL) have molecular structures capable of chemical signalling that regulate gene expression, metabolism and inflammation. This study sets out to assess how CNSL derivatives impact oral bacteria, from an antibacterial and anti-collagenolytic perspective, as well as its biocompatibility with dental pulp stem cells. Two hemi-synthetic saturated CNSL derivative compounds were selected (LDT11-Anacardic Acids-derivative and LDT409-cardanol-derivative). Bacteriostatic activity was tested against Streptococcus mutans and Veillonella parvula. Antimicrobial capacity against preformed S. mutans biofilms was investigated using a collagen-coated Calgary Biofilm Device and confocal microscopy. Clostridium histolyticum, P. gingivalis and S. mutans biofilms were used to assess anti-collagenolytic activity. Biocompatibility with human dental pulp stromal cells (HDPSCs) was investigated (MTT for viability proportion, LDH assays for cell death rate). LDTs inhibited the bacterial growth, as well as partially inhibited bacterial collagenases in concentrations higher than 5 µg/mL. Dose-response rates of biofilm cell death was observed (LDT11 at 20, 50, 100 µg/mL = 1.0 ± 0.4, 0.7 ± 0.3, 0.6 ± 0.03, respectively). Maximum cytotoxicity was 30%. After 1 week, LDT409 had no HDPSCs death. HDPSCs viability was decreased after 24 h of treatment with LDT11 and LDT409, but recovered at 72 h and showed a massive increase in viability and proliferation after 1 week. LDTs treatment was associated with odontoblast-like morphology. In conclusion, LDT11 multifunctionality and biocompatibility, stimulating dental pulp stem cells proliferation and differentiation, indicates a potential as a bio-based dental material for regenerative Dentistry. Its potential as a bacterial collagenases inhibitor to reduce collagen degradation in root/dentinal caries can be further explored.

Cashew Nut Shell Liquid (CNSL) as a Source of Drugs for Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder with a multifaceted pathogenesis. This fact has long halted the development of effective anti-AD drugs. Recently, a therapeutic strategy based on the exploitation of Brazilian biodiversity was set with the aim of discovering new disease-modifying and safe drugs for AD. In this review, we will illustrate our efforts in developing new molecules derived from Brazilian cashew nut shell liquid (CNSL), a natural oil and a byproduct of cashew nut food processing, with a high content of phenolic lipids. The rational modification of their structures has emerged as a successful medicinal chemistry approach to the development of novel anti-AD lead candidates. The biological profile of the newly developed CNSL derivatives towards validated AD targets will be discussed together with the role of these molecular targets in the context of AD pathogenesis.

Novel Sustainable-by-Design HDAC Inhibitors for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) represents a global problem, with an estimation of the majority of dementia patients in low- and middle-income countries by 2050. Thus, the development of sustainable drugs has attracted much attention in recent years. In light of this, taking inspiration from the HDAC inhibitor vorinostat (1), we develop the first HDAC inhibitors derived from cashew nut shell liquid (CNSL), an inexpensive agro-food waste material. CNSL derivatives 8 and 9 display a HDAC inhibitory profile similar to 1, together with a more promising safety for 9 compared to 1. Moreover, both compounds and particularly 9 were able to effectively modulate glial cell-induced inflammation and to revert the pro-inflammatory phenotype. All these results demonstrate that the use of inexpensive food waste materials could be successfully applied for the development of accessible and sustainable drug candidates for the treatment of AD.

Synthesis and structure-activity relationships of novel arylpiperazines as potent antagonists of α1-adrenoceptor.

Arylpiperazines 2-11 were synthesized, and their biological profiles at α1-adrenergic receptors (α1-ARs) assessed by binding assays in CHO cells expressing human cloned subtypes and by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Modifications at the 1,3-benzodioxole and phenyl phamacophoric units resulted in the identification of a number of potent compounds (moderately selective with respect to the α1b-AR), in binding experiments. Notably, compound 7 (LDT451) showed a subnanomolar pKi of 9.41 towards α1a-AR. An encouragingly lower α1B-potency was a general trend for all the series of compounds, which showed α1A/D over α1B selectivity in functional assays. If adequately optimized, such peculiar selectivity could have relevance for a potential LUTS/BPH therapeutic application.

Cardanol-derived AChE inhibitors: Towards the development of dual binding derivatives for Alzheimer's disease.

Cardanol is a phenolic lipid component of cashew nut shell liquid (CNSL), obtained as the byproduct of cashew nut food processing. Being a waste product, it has attracted much attention as a precursor for the production of high-value chemicals, including drugs. On the basis of these findings and in connection with our previous studies on cardanol derivatives as acetylcholinesterase (AChE) inhibitors, we designed a novel series of analogues by including a protonable amino moiety belonging to different systems. Properly addressed docking studies suggested that the proposed structural modifications would allow the new molecules to interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, thus being able to act as dual binding inhibitors. To disclose whether the new molecules showed the desired profile, they were first tested for their cholinesterase inhibitory activity towards EeAChE and eqBuChE. Compound 26, bearing an N-ethyl-N-(2-methoxybenzyl)amine moiety, showed the highest inhibitory activity against EeAChE, with a promising IC50 of 6.6 µM, and a similar inhibition profile of the human isoform (IC50 = 5.7 µM). As another positive feature, most of the derivatives did not show appreciable toxicity against HT-29 cells, up to a concentration of 100 µM, which indicates drug-conform behavior. Also, compound 26 is capable of crossing the blood-brain barrier (BBB), as predicted by a PAMPA-BBB assay. Collectively, the data suggest that the approach to obtain potential anti-Alzheimer drugs from CNSL is worth of further pursuit and development.