A review on natural sweeteners, sweet taste modulators and bitter masking compounds: structure-activity strategies for the discovery of novel taste molecules.

Growing demand for the tasty and healthy food has driven the development of low-calorie sweeteners, sweet taste modulators, and bitter masking compounds originated from natural sources. With the discovery of human taste receptors, increasing numbers of sweet taste modulators have been identified through human taste response and molecular docking techniques. However, the discovery of novel taste-active molecules in nature can be accelerated by using advanced spectrometry technologies based on structure-activity relationships (SARs). SARs explain why structurally similar compounds can elicit similar taste qualities. Given the characterization of structural information from reported data, strategies employing SAR techniques to find structurally similar compounds become an innovative approach to expand knowledge of sweeteners. This review aims to summarize the structural patterns of known natural non-nutritive sweeteners, sweet taste enhancers, and bitter masking compounds. Innovative SAR-based approaches to explore sweetener derivatives are also discussed. Most sweet-tasting flavonoids belong to either the flavanonols or the dihydrochalcones and known bitter masking molecules are flavanones. Based on SAR findings that structural similarities are related to the sensory properties, innovative methodologies described in this paper can be applied to screen and discover the derivatives of taste-active compounds or potential taste modulators.

Design and synthesis of sirtinol analogs as human neutrophil elastase inhibitors.

Human neutrophil elastase (HNE) overexpression has a crucial role in most acute inflammation and alpha1-antitrypsin deficiency syndromes observed in humans, triggering neutrophil invasion and activation of macrophage inflammatory and proteolytic effects, leading to tissue damage. Manipulating HNE level homeostasis could potentially help treat neutrophilic inflammation. Previous studies have shown that sirtinol (1) has a specific influence on HNE and potently attenuates acute lung injury and hepatic injury mediated by lipopolysaccharide or trauma hemorrhage. Therefore, 1 was chosen as the model structure to obtain more potent anti-HNE agents. In the present study, we synthesized a series of sirtinol analogues and determined their inhibitory effects on HNE. Structure-activity relationship (SAR) studies showed that swapping the imine and methyl groups of the sirtinol scaffold with diazene and carboxyl groups, respectively, enhances the HNE inhibiting potency. Compound 29 exhibited the highest potency in the SAR study and showed dual inhibitory effects on HNE and proteinase 3 with IC50 values of 4.91 and 20.69 µM, respectively. Furthermore, 29 was confirmed to have dual impacts on inhibiting O2•- generation and elastase release in cell-based assays with IC50 values of 0.90 and 1.86 µM, respectively. These findings suggest that 29 is a promising candidate for developing HNE inhibitors in the treatment of neutrophilic inflammatory diseases.

A comprehensive review of synthetic strategies and SAR studies for the discovery of PfDHODH inhibitors as antimalarial agents. Part 1: triazolopyrimidine, isoxazolopyrimidine and pyrrole-based (DSM) compounds.

One of the deadliest infectious diseases, malaria, still has a significant impact on global morbidity and mortality. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the fourth step in de novo pyrimidine nucleotide biosynthesis and has been clinically validated as an innovative and promising target for the development of novel targeted antimalarial drugs. PfDHODH inhibitors have the potential to significantly slow down parasite growth at the blood and liver stages. Several PfDHODH inhibitors based on various scaffolds have been explored over the past two decades. Among them, triazolopyrimidines, isoxazolopyrimidines, and pyrrole-based derivatives known as DSM compounds showed tremendous potential as novel antimalarial agents, and one of the triazolopyrimidine-based compounds (DSM265) was able to reach phase IIa clinical trials. DSM compounds were synthesized as PfDHODH inhibitors with various substitutions based on structure-guided medicinal chemistry approaches and further optimised as well. For the first time, this review provides an overview of all the synthetic approaches used for the synthesis, alternative synthetic routes, and novel strategies involving various catalysts and chemical reagents that have been used to synthesize DSM compounds. We have also summarized SAR study of all these PfDHODH inhibitors. In an attempt to assist readers, scientists, and researchers involved in the development of new PfDHODH inhibitors as antimalarials, this review provides accessibility of all synthetic techniques and SAR studies of the most promising triazolopyrimidines, isoxazolopyrimidines, and pyrrole-based PfDHODH inhibitors.

Platanosides from Platanus × acerifolia: New molecules, SAR, and target validation of a strong lead for drug-resistant bacterial infections and the associated sepsis.

Three undescribed (1-3) and nine known (4-12) platanosides were isolated and characterized from a bioactive extract of the May leaves of Platanus × acerifolia that initially showed inhibition against Staphylococcus aureus. Targeted compound mining was guided by an LC-MS/MS-based molecular ion networking (MoIN) strategy combined with conventional isolation procedures from a unique geographic location. The novel structures were mainly determined by 2D NMR and computational (NMR/ECD calculations) methods. Compound 1 is a rare acylated kaempferol rhamnoside possessing a truxinate unit. 6 (Z,E-platanoside) and 7 (E,E-platanoside) were confirmed to have remarkable inhibitory effects against both methicillin-resistant S. aureus (MIC: ≤ 16 µg/mL) and glycopeptide-resistant Enterococcus faecium (MIC: ≤ 1 µg/mL). These platanosides were subjected to docking analyses against FabI (enoyl-ACP reductase) and PBP1/2 (penicillin binding protein), both of which are pivotal enzymes governing bacterial growth but not found in the human host. The results showed that 6 and 7 displayed superior binding affinities towards FabI and PBP2. Moreover, surface plasmon resonance studies on the interaction of 1/7 and FabI revealed that 7 has a higher affinity (KD = 1.72 µM), which further supports the above in vitro data and is thus expected to be a novel anti-antibacterial drug lead.

Antidiabetic potential of thiazolidinedione derivatives with efficient design, molecular docking, structural activity relationship, and biological activity: an update review (2021-2023).

Thiazolidinedione has been used successfully by medicinal chemists all over the world in the development of potent antidiabetic derivatives. The few compounds with excellent antidiabetic potency that we have identified in this review could be used as a lead for further research into additional antidiabetic mechanisms. The information provided in this review regarding the design, biological activity, structure-activity relationships, and docking studies may be useful for scientists who wish to further explore this scaffold in order to fully utilize its biological potential and develop antidiabetic agents that would overcome the limitations of currently available medications for the treatment of diabetes. This review outlines the antidiabetic potential of Thiazolidinedione-based derivatives that have been published in the year 2021- till date.

Determining recommended acceptable intake limits for N-nitrosamine impurities in pharmaceuticals: Development and application of the Carcinogenic Potency Categorization Approach (CPCA).

N-Nitrosamine impurities, including nitrosamine drug substance-related impurities (NDSRIs), have challenged pharmaceutical industry and regulators alike and affected the global drug supply over the past 5 years. Nitrosamines are a class of known carcinogens, but NDSRIs have posed additional challenges as many lack empirical data to establish acceptable intake (AI) limits. Read-across analysis from surrogates has been used to identify AI limits in some cases; however, this approach is limited by the availability of robustly-tested surrogates matching the structural features of NDSRIs, which usually contain a diverse array of functional groups. Furthermore, the absence of a surrogate has resulted in conservative AI limits in some cases, posing practical challenges for impurity control. Therefore, a new framework for determining recommended AI limits was urgently needed. Here, the Carcinogenic Potency Categorization Approach (CPCA) and its supporting scientific rationale are presented. The CPCA is a rapidly-applied structure-activity relationship-based method that assigns a nitrosamine to 1 of 5 categories, each with a corresponding AI limit, reflecting predicted carcinogenic potency. The CPCA considers the number and distribution of α-hydrogens at the N-nitroso center and other activating and deactivating structural features of a nitrosamine that affect the α-hydroxylation metabolic activation pathway of carcinogenesis. The CPCA has been adopted internationally by several drug regulatory authorities as a simplified approach and a starting point to determine recommended AI limits for nitrosamines without the need for compound-specific empirical data.

Dehydroacetic acid a privileged medicinal scaffold: A concise review.

From the last decade, research on dehydroacetic acid (DHA) and its derivatives has increased immensely due to its significant role in various fields, including medicine, cosmetics, food industry, and so on. In the medicinal area, DHA plays an essential role in developing novel action-based drugs, which are helpful for treating various diseases. Besides its plethora of biological applications, its chelating ability offers the easiest synthetic route for synthesizing more active metal complexes. DHA derivatives along with their metal complexes show a number of biological activities and also exhibit various interactions with multiple biological targets. This article summarizes recent medicinal applications (2000-onwards) of DHA-based compounds and their analogs, along with their structure-activity relationship (SAR) analysis. Their interactions with different target enzymes are also discussed. This information derived from SAR analysis would be helpful for medicinal chemists working on the development of drugs based on heterocyclic frameworks, particularly those based on the DHA scaffold.

Synthesis, biological activities, and structure-activity relationships of Morita-Baylis-Hillman adducts: An update.

The Morita-Baylis-Hillman (MBH) reaction is a unique C-C bond-forming technique for the generation of multifunctional allylic alcohols (MBH adducts) in a single operation. In recent years, these MBH adducts have emerged as a novel class of compounds with significant biological potential, including anticancer, anti-leishmanial, antibacterial, antifungal, anti-herbicidal effects and activity against Chagas disease, and so on. The aim of this review is to assimilate the literature findings from 2011 onwards related to the synthesis and biological potential of MBH adducts, with an emphasis on their structure-activity relationships (SAR). Although insight into the biological mechanisms of action for this recently identified pharmacophore is currently in its nascent stages, the mechanisms described so far are reviewed herein.

Evaluation of the Therapeutic Potential of Sulfonyl Urea Derivatives as Soluble Epoxide Hydrolase (sEH) Inhibitors.

The inhibition of soluble epoxide hydrolase (sEH) can reduce the level of dihydroxyeicosatrienoic acids (DHETs) effectively maintaining endogenous epoxyeicosatrienoic acids (EETs) levels, resulting in the amelioration of inflammation and pain. Consequently, the development of sEH inhibitors has been a prominent research area for over two decades. In the present study, we synthesized and evaluated sulfonyl urea derivatives for their potential to inhibit sEH. These compounds underwent extensive in vitro investigation, revealing their potency against human and mouse sEH, with 4f showing the most promising sEH inhibitory potential. When subjected to lipopolysaccharide (LPS)-induced acute lung injury (ALI) in studies in mice, compound 4f manifested promising anti-inflammatory efficacy. We investigated the analgesic efficacy of sEH inhibitor 4f in a murine pain model of tail-flick reflex. These results validate the role of sEH inhibition in inflammatory diseases and pave the way for the rational design and optimization of sEH inhibitors based on a sulfonyl urea template.

SAR, Molecular Docking and Molecular Dynamic Simulation of Natural Inhibitors against SARS-CoV-2 Mpro Spike Protein.

The SARS-CoV-2 virus and its mutations have affected human health globally and created significant danger for the health of people all around the world. To cure this virus, the human Angiotensin Converting Enzyme-2 (ACE2) receptor, the SARS-CoV-2 main protease (Mpro), and spike proteins were found to be likely candidates for the synthesis of novel therapeutic drug. In the past, proteins were capable of engaging in interaction with a wide variety of ligands, including both manmade and plant-derived small molecules. Pyrus communis L., Ginko bibola, Carica papaya, Syrian rue, and Pimenta dioica were some of the plant species that were studied for their tendency to interact with SARS-CoV-2 main protease (Mpro) in this research project (6LU7). This scenario investigates the geometry, electronic, and thermodynamic properties computationally. Assessing the intermolecular forces of phytochemicals with the targets of the SARS-CoV-2 Mpro spike protein (SP) resulted in the recognition of a compound, kaempferol, as the most potent binding ligand, -7.7 kcal mol-1. Kaempferol interacted with ASP-187, CYS-145, SER-144, LEU 141, MET-165, and GLU-166 residues. Through additional molecular dynamic simulations, the stability of ligand-protein interactions was assessed for 100 ns. GLU-166 remained intact with 33% contact strength with phenolic OH group. We noted a change in torsional conformation, and the molecular dynamics simulation showed a potential variation in the range from 3.36 to 7.44 against a 45-50-degree angle rotation. SAR, pharmacokinetics, and drug-likeness characteristic investigations showed that kaempferol may be the suitable candidate to serve as a model for designing and developing new anti-COVID-19 medicines.

Boosting of retinol activity using novel lecithin: Retinol acyltransferase inhibitors.

Lecithin:retinol acyltransferase (LRAT) is the main enzyme catalysing the esterification of retinol to retinyl esters and, hence, is of central importance for retinol homeostasis. As retinol, by its metabolite retinoic acid, stimulates fibroblasts to synthesize collagen fibres and inhibits collagen-degrading enzymes, the inhibition of LRAT presents an intriguing strategy for anti-ageing ingredients by increasing the available retinol in the skin. Here, we synthesized several derivatives mimicking natural lecithin substrates as potential LRAT inhibitors. By exploring various chemical modifications of the core scaffold consisting of a central amino acid and an N-terminal acylsulfone, we explored 10 different compounds in a biochemical assay, resulting in two compounds with IC50 values of 21.1 and 32.7 µM (compounds 1 and 2), along with a simpler arginine derivative with comparative inhibitory potency. Supported by computational methods, we investigated their structure-activity relationship, resulting in the identification of several structural features associated with high inhibition of LRAT. Ultimately, we conducted an ex vivo study with human skin, demonstrating an increase of collagen III associated with a reduction of the skin ageing process. In conclusion, the reported compounds offer a promising approach to boost retinol abundance in human skin and might present a new generation of anti-ageing ingredients for cosmetic application.

La lécithine/rétinol acyltransférase (LRAT) est la principale enzyme qui catalyse l'estérification du rétinol en esters de rétinyle et, par conséquent, est d'une importance centrale pour l'homéostasie du rétinol. Étant donné que le rétinol, par son métabolite l'acide rétinoïque, stimule les fibroblastes pour synthétiser les fibres de collagène et inhibe les enzymes de dégradation du collagène, l'inhibition de la LRAT constitue une stratégie intéressante pour les ingrédients anti­âge en augmentant le rétinol disponible dans la peau. Ici, nous avons synthétisé plusieurs dérivés imitant les substrats naturels de la lécithine comme inhibiteurs de LRAT potentiels. En étudiant différentes modifications chimiques du noyau composé d'un acide aminé central et d'un acylsulfone N­terminal, nous avons étudié dix composés différents dans le cadre d'un essai biochimique; il en est résulté deux composés avec des valeurs de CI50 de 21.1 et 32.7 µm (composés 1 et 2), ainsi qu'un dérivé d'arginine plus simple avec une puissance inhibitrice comparative. Avec le soutien de méthodes computationnelles, nous avons étudié leur relation structure­activité, ce qui a permis d'identifier plusieurs caractéristiques structurelles associées à une inhibition élevée de la LRAT. Enfin, nous avons mené une étude ex vivo sur la peau humaine, démontrant une augmentation du collagène III associée à une réduction du processus de vieillissement de la peau. En conclusion, les composés rapportés offrent une approche prometteuse pour stimuler l'abondance du rétinol dans la peau humaine et pourraient aboutir à une nouvelle génération d'ingrédients anti­âge pour des applications cosmétiques.

Assessment of the inhibition risk of chlorophenol substances on cytochrome P450 via cocktail inhibition assays.

Chlorophenols (CPs) are widespread pollutants in nature. CPs have raised significant concern due to their potential hepatotoxic effects on humans. This research aimed to ascertain the inhibitory potential of eleven CPs (2-CP, 3-CP, 4-CP, 2,4-DCP, 2,3,4-TCP, 2,4,5-TCP, 2,4,6-TCP, 2,3,4,5-TeCP, 2,3,4,6-TeCP, 2,3,5,6-TeCP, and PCP) on nine human CYP isoforms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4). The CPs that inhibit the activity of CYP isoforms were detected with human liver microsomes (HLM) using a cocktail approach in vitro. The results demonstrated that trichlorophenols, tetrachlorophenols, and PCP strongly inhibited CYP2C8 and CYP2C9. The half inhibition concentration (IC50) value of 2,3,4,6-TeCP and PCP for CYP2C8 inhibition was 27.3 µM and 12.3 µM, respectively. The IC50 for the inhibition of 2,4,6-TCP, 2,3,4,6-TeCP and PCP towards CYP2C9 were calculated to be 30.3 µM, 5.8 µM and 2.2 µM, respectively. 2,3,4,6-TeCP, and PCP exhibited non-competitive inhibition towards CYP2C8. 2,4,6-TCP, 2,3,4,6-TeCP, and PCP exhibited competitive inhibition towards CYP2C9. The inhibition kinetics parameters (Ki) were 51.51 µM, 22.28 µM, 37.86 µM, 7.27 µM, 0.68 µM for 2,3,4,6-TeCP-CYP2C8, PCP-CYP2C8, 2,4,6-TCP-CYP2C9, 2,3,4,6-TeCP-CYP2C9, PCP-CYP2C9, respectively. This study also defined clear structure-activity relationships (SAR) of CPs on CYP2C8, supported by molecular docking studies. Overall, CPs were found to cause inhibitory effects on CYP isoforms in vitro, and this finding may provide a basis for CPs focused on CYP isoforms inhibition endpoints.

Benzimidazole derivatives as tubulin polymerization inhibitors: Design, synthesis and in vitro cytotoxicity studies.

A new class of benzimidazole derivatives as tubulin polymerization inhibitors has been designed and synthesized in this study. The in vitro anticancer profile of the developed molecules was reconnoitred on selected human cancer cells. The highest cytotoxicity was illustrated by compounds 7n and 7u with IC50 values ranging from 2.55 to 17.89 µM with specificity toward SK-Mel-28 cells. They displayed 5-fold less cytotoxicity towards normal rat kidney epithelial NRK52E cells, which implies that they are not harmful to normal, healthy cells. The cellular staining procedures like AO/EB, DCFDA, and DAPI were applied to comprehend the inherent mechanism of apoptosis which displayed nuclear and morphological alterations. The Annexin V binding and JC-1 studies were executed to evaluate the extent of apoptosis and the decline in mitochondrial transmembrane potential in SK-Mel-28 cell lines. Compound 7n dose-dependently arrested the G2/M phase of the cell cycle and the target-based outcomes proposed tubulin polymerization inhibition by 7n (IC50 of 5.05±0.13 µM). Computational studies were also conducted on the tubulin protein (PDB ID: 3E22) to investigate the stabilized binding interactions of compounds 7n and 7u with tubulin, respectively.

Synthesis and SAR of a novel Kir6.2/SUR1 channel opener scaffold identified by HTS.

Kir6.2/SUR1 is an ATP-regulated potassium channel that acts as an intracellular metabolic sensor, controlling insulin and appetite-stimulatory neuropeptides secretion. In this Letter, we present the SAR around a novel Kir6.2/SUR1 channel opener scaffold derived from an HTS screening campaign. New series of compounds with tractable SAR trends and favorable potencies are reported.

Design and synthesis of aminopyridine containing biaryls reducing c-MYC protein levels in cells.

The c-MYC oncogene transcription factor has been implicated in cell cycle regulation controlling cell growth and proliferation. It is tightly regulated in normal cells, but has been shown to be deregulated in cancer cells, and is thus an attractive target for oncogenic therapies. Building upon previous SAR, a series of analogues containing benzimidazole core replacements were prepared and evaluated, leading to the identification of imidazopyridazine compounds that were shown to possess equivalent or improved c-MYC HTRF pEC50 values, lipophilicity, solubility, and rat pharmacokinetics. The imidazopyridazine core was therefore determined to be superior to the original benzimidazole core and a viable alternate for continued lead optimization and medicinal chemistry campaigns.

Synthesis, evaluation of anti-breast cancer activity in vitro of ICS II derivatives and summary of the structure-activity relationship.

A series of Icariside II (ICS II) derivatives were synthesized, and their structure-activity relationships (SARs) were studied in this paper. The in vitro antitumor activities towards human breast cancer cell lines (MCF-7) were evaluated by Cell Counting Kit-8 (CCK-8 kit). Preliminary results showed that, compared with ICS II, most of the derivatives displayed good micromole level activities. Among the series of derivatives, the S27, which totally acetylated hydroxyl of ICS II, possessed highest cytotoxicity, with IC50 values of 0.70 ± 0.08 µM. Furthermore, compound S27 showed better selectivity than ICS II for cancer cells over normal cells. Our findings indicate that compound S27 may be a promising anticancer lead candidate drug.

Classification models and SAR analysis on HDAC1 inhibitors using machine learning methods.

Histone deacetylase (HDAC) 1, a member of the histone deacetylases family, plays a pivotal role in various tumors. In this study, we collected 7313 human HDAC1 inhibitors with bioactivities to form a dataset. Then, the dataset was divided into a training set and a test set using two splitting methods: (1) Kohonen's self-organizing map and (2) random splitting. The molecular structures were represented by MACCS fingerprints, RDKit fingerprints, topological torsions fingerprints and ECFP4 fingerprints. A total of 80 classification models were built by using five machine learning methods, including decision tree (DT), random forest, support vector machine, eXtreme Gradient Boosting and deep neural network. Model 15A_2 built by the XGBoost algorithm based on ECFP4 fingerprints showed the best performance, with an accuracy of 88.08% and an MCC value of 0.76 on the test set. Finally, we clustered the 7313 HDAC1 inhibitors into 31 subsets, and the substructural features in each subset were investigated. Moreover, using DT algorithm we analyzed the structure-activity relationship of HDAC1 inhibitors. It may conclude that some substructures have a significant effect on high activity, such as N-(2-amino-phenyl)-benzamide, benzimidazole, AR-42 analogues, hydroxamic acid with a middle chain alkyl and 4-aryl imidazole with a midchain of alkyl whose α carbon is chiral.

Classification models for predicting the bioactivity of pan-TRK inhibitors and SAR analysis.

Tropomyosin receptor kinases (TRKs) are important broad-spectrum anticancer targets. The oncogenic rearrangement of the NTRK gene disrupts the extracellular structural domain and epitopes for therapeutic antibodies, making small-molecule inhibitors essential for treating NTRK fusion-driven tumors. In this work, several algorithms were used to construct descriptor-based and nondescriptor-based models, and the models were evaluated by outer 10-fold cross-validation. To find a model with good generalization ability, the dataset was partitioned by random and cluster-splitting methods to construct in- and cross-domain models, respectively. Among the 48 models built, the model with the combination of the deep neural network (DNN) algorithm and extended connectivity fingerprints 4 (ECFP4) descriptors achieved excellent performance in both dataset divisions. The results indicate that the DNN algorithm has a strong generalization prediction ability, and the richness of features plays a vital role in predicting unknown spatial molecules. Additionally, we combined the clustering results and decision tree models of fingerprint descriptors to perform structure-activity relationship analysis. It was found that nitrogen-containing aromatic heterocyclic and benzo heterocyclic structures play a crucial role in enhancing the activity of TRK inhibitors. Workflow for generating predictive models for TRK inhibitors.

Synthesis and biological evaluation of C-4 substituted phenoxazine-bearing hydroxamic acids with potent class II histone deacetylase inhibitory activities.

Class II histone deacetylases (HDACs) are considered as potential targets to treat Alzheimer's disease (AD). Previously, C-3 substituted phenothiazine-containing compounds with class II HDAC-inhibiting activities was found to promote neurite outgrowth. This study replaced phenothiazine moiety with phenoxazine that contains many C-3 and C-4 substituents. Some resulting compounds bearing the C-4 substituent on a phenoxazine ring displayed potent class II HDAC inhibitory activities. Structure-activity relationship (SAR) of these compounds that inhibited HDAC isoenzymes was disclosed. Molecular modelling analysis demonstrates that the potent activities of C-4 substituted compounds probably arise from π-π stacked interactions between these compounds and class IIa HDAC enzymes. One of these, compound 7d exhibited the most potent class II HDAC inhibition (IC50= 3-870 nM). Notably, it protected neuron cells from H2O2-induced neuron damage at sub-µM concentrations, but with no significant cytotoxicity. These findings show that compound 7d is a lead compound for further development of anti-neurodegenerative agents.

Theonella: A Treasure Trove of Structurally Unique and Biologically Active Sterols.

The marine environment is considered a vast source in the discovery of structurally unique bioactive secondary metabolites. Among marine invertebrates, the sponge Theonella spp. represents an arsenal of novel compounds ranging from peptides, alkaloids, terpenes, macrolides, and sterols. In this review, we summarize the recent reports on sterols isolated from this amazing sponge, describing their structural features and peculiar biological activities. We also discuss the total syntheses of solomonsterols A and B and the medicinal chemistry modifications on theonellasterol and conicasterol, focusing on the effect of chemical transformations on the biological activity of this class of metabolites. The promising compounds identified from Theonella spp. possess pronounced biological activity on nuclear receptors or cytotoxicity and result in promising candidates for extended preclinical evaluations. The identification of naturally occurring and semisynthetic marine bioactive sterols reaffirms the utility of examining natural product libraries for the discovery of new therapeutical approach to human diseases.