In silico study suggests potential drugs that target CD151 to treat breast cancer and lioblastoma.

Recently tetraspanin CD151 has been identified as an important biological target involved in metastatic processes which include cell adhesion, tumor progression processes, and so forth in different types of cancers, such as breast cancer and glioblastoma. This in Silico study considered 1603 compounds from the Food and Drug Administration database, after performing an ADMET analysis; we selected 853 ligands, which were used for docking analysis. The most promising ligands were selected from docking studies, based on two criteria: (a) showed lowest affinity to the CD151 protein and (b) they interact with the QRD motif, located in the second extracellular loop. Furthermore, we investigate the stability of the protein-ligand complexes through MD simulations as well as free energy MM-PBSA calculations. From these results, loperamide and glipizide were identified as the best evaluated drugs. We suggest an in vitro analysis is needed to confirm our in silico prediction studies.

Untargeted LC-MS/MS Metabolomics Study of HO-AAVPA and VPA on Breast Cancer Cell Lines.

Breast cancer (BC) is one of the biggest health problems worldwide, characterized by intricate metabolic and biochemical complexities stemming from pronounced variations across dysregulated molecular pathways. If BC is not diagnosed early, complications may lead to death. Thus, the pursuit of novel therapeutic avenues persists, notably focusing on epigenetic pathways such as histone deacetylases (HDACs). The compound N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA), a derivative of valproic acid (VPA), has emerged as a promising candidate warranting pre-clinical investigation. HO-AAVPA is an HDAC inhibitor with antiproliferative effects on BC, but its molecular mechanism has yet to be deciphered. Furthermore, in the present study, we determined the metabolomic effects of HO-AAVPA and VPA on cells of luminal breast cancer (MCF-7) and triple-negative breast cancer (MDA-MB-231) subtypes. The LC-MS untargeted metabolomic study allowed for the simultaneous measurement of multiple metabolites and pathways, identifying that both compounds affect glycerophospholipid and sphingolipid metabolism in the MCF-7 and MDA-MB-231 cell lines, suggesting that other biological targets were different from HDACs. In addition, there are different dysregulate metabolites, possibly due to the physicochemical differences between HO-AAVPA and VPA.

Targeting Several Biologically Reported Targets of Glioblastoma Multiforme by Assaying 2D and 3D Cultured Cells.

Glioblastoma multiforme (GBM) is account for 70% of all primary malignancies of the central nervous system. The median survival of human patients after treatment is around 15 months. There are several biological targets which have been reported that can be pursued using ligands with varied structures to treat this disease. In our group, we have developed several ligands that target a wide range of proteins involved in anticancer effects, such as histone deacetylase (HDACs), G protein-coupled estrogen receptor 1 (GPER), estrogen receptor-beta (ERß) and NADPH oxidase (NOX), that were screened on bidimensional (2D) and tridimensional (3D) GBM stem cells like (GSC). Our results show that some HDAC inhibitors show antiproliferative properties at 21-32 µM. These results suggest that in this 3D culture, HDACs could be the most relevant targets that are modulated to induce the antiproliferative effects that require in the future further experimental studies.

LC-MS Based Lipidomics Depict Phosphatidylethanolamine as Biomarkers of TNBC MDA-MB-231 over nTNBC MCF-7 Cells.

Breast cancer (BC) is the first malignant neoplasm in women, with a high death rate despite early diagnoses and treatment advances. Significant differences exist between the most common BC and triple-negative breast cancer (TNBC). TNBC presents molecular differences such as lacking expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 proteins, making this cancer have a poor clinical prognostic and lack clear strategies for its treatment. However, growing evidence points to metabolic dysregulation as another differential process between stages and types of BC. Therefore, the study of this crucial hallmark could identify new therapeutic targets to treat this aggressive form of BC. These differences induce an in vitro exploration of the metabolic behavior of the MCF7 cells (nTNBC) and MDA-MB-231 (TNBC) cells under lipidomic based LC-MS. The results show more significant differences in lipid regulation (phosphatidylethanolamine) that could be associated with the aggressiveness and difficulties of the treatment of TNBC.

Untargeted LC-MS/MS Metabolomics Study on the MCF-7 Cell Line in the Presence of Valproic Acid.

To target breast cancer (BC), epigenetic modulation could be a promising therapy strategy due to its role in the genesis, growth, and metastases of BC. Valproic acid (VPA) is a well-known histone deacetylase inhibitor (HDACi), which due to its epigenetic focus needs to be studied in depth to understand the effects it might elicit in BC cells. The aim of this work is to contribute to exploring the complete pharmacological mechanism of VPA in killing cancer cells using MCF-7. LC-MS/MS metabolomics studies were applied to MCF-7 treated with VPA. The results show that VPA promote cell death by altering metabolic pathways principally pentose phosphate pathway (PPP) and 2'deoxy-α-D-ribose-1-phosphate degradation related with metabolites that decrease cell proliferation and cell growth, interfere with energy sources and enhance reactive oxygen species (ROS) levels. We even suggest that mechanisms such as ferropoptosis could be involved due to deregulation of L-cysteine. These results suggest that VPA has different pharmacological mechanisms in killing cancer cells including apoptotic and nonapoptotic mechanisms, and due to the broad impact that HDACis have in cells, metabolomic approaches are a great source of information to generate new insights for this type of molecule.

In Silico and In Vitro Studies of Benzothiazole-Isothioureas Derivatives as a Multitarget Compound for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Inhibiting acetylcholinesterase (AChE), amyloid beta (Aß1-42) aggregation and avoiding the oxidative stress could prevent the progression of AD. Benzothiazole groups have shown neuroprotective activity whereas isothioureas groups act as AChE inhibitors and antioxidants. Therefore, 22 benzothiazole-isothiourea derivatives (3a-v) were evaluated by docking simulations as inhibitors of AChE and Aß1-42 aggregation. In silico studies showed that 3f, 3r and 3t had a delta G (ΔG) value better than curcumin and galantamine on Aß1-42 and AChE, respectively. The physicochemical and pharmacokinetics predictions showed that only 3t does not violate Lipinski's rule of five, though it has moderated cytotoxicity activity. Then, 3f, 3r and 3t were synthetized and chemically characterized for their in vitro evaluation including their antioxidant activity and their cytotoxicity in PC12 cells. 3r was able to inhibit AChE, avoid Aß1-42 aggregation and exhibit antioxidant activity; nevertheless, it showed cytotoxic against PC12 cells. Compound 3t showed the best anti-Aß1-42 aggregation and inhibitory AChE activity and, despite that predictor, showed that it could be cytotoxic; in vitro with PC12 cell was negative. Therefore, 3t could be employed as a scaffold to develop new molecules with multitarget activity for AD and, due to physicochemical and pharmacokinetics predictions, it could be administered in vivo using liposomes due to is not able to cross the BBB.

Synthesis and Biological Importance of 2-(thio)ureabenzothiazoles.

The (thio)urea and benzothiazole (BT) derivatives have been shown to have a broad spectrum of biological activities. These groups, when bonded, result in the 2-(thio)ureabenzothizoles (TBT and UBT), which could favor the physicochemical and biological properties. UBTs and TBTs are compounds of great importance in medicinal chemistry. For instance, Frentizole is a UBT derivative used for the treatment of rheumatoid arthritis and systemic lupus erythematosus. The UBTs Bentaluron and Bethabenthiazuron are commercial fungicides used as wood preservatives and herbicides in winter corn crops. On these bases, we prepared this bibliography review, which covers chemical aspects of UBTs and TBTs as potential therapeutic agents as well as their studies on the mechanisms of a variety of pharmacological activities. This work covers synthetic methodologies from 1935 to nowadays, highlighting the most recent approaches to afford UBTs and TBTs with a variety of substituents as illustrated in 42 schemes and 13 figures and concluded with 187 references. In addition, this interesting review is designed on chemical reactions of 2-aminobenzothiazoles (2ABTs) with (thio)phosgenes, iso(thio)cyanates, 1,1'-(thio)carbonyldiimidazoles [(T)CDI]s, (thio)carbamoyl chlorides, and carbon disulfide. This topic will provide information of utility for medicinal chemists dedicated to the design and synthesis of this class of compounds to be tested with respect to their biological activities and be proposed as new pharmacophores.

Preclinical Pharmacokinetics and Acute Toxicity in Rats of 5-{[(2E)-3-Bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic Acid: A Novel 5-Aminosalicylic Acid Derivative with Potent Anti-Inflammatory Activity.

Compound 5-{[(2E)-3-bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic acid (C1), a new 5-aminosalicylic acid (5-ASA) derivative, has proven to be an antioxidant in vitro and an anti-inflammatory agent in mice. The in vivo inhibition of myeloperoxidase was comparable to that of indomethacin. The aim of this study was to take another step in the preclinical evaluation of C1 by examining acute toxicity with the up-and-down OECD method and pharmacokinetic profiles by administration of the compound to Wistar rats through intravenous (i.v.), oral (p.o.), and intraperitoneal (i.p.) routes. According to the Globally Harmonized System, C1 belongs to categories 4 and 5 for the i.p. and p.o. routes, respectively. An RP-HPLC method for C1 quantification in plasma was successfully validated. Regarding the pharmacokinetic profile, the elimination half-life was approximately 0.9 h with a clearance of 24 mL/min after i.v. administration of C1 (50 mg/kg). After p.o. administration (50 mg/kg), the maximum plasma concentration was reached at 33 min, the oral bioavailability was about 77%, and the compound was amply distributed to all tissues evaluated. Therefore, C1 administered p.o. in rats is suitable for reaching the colon where it can exert its effect, suggesting an important advantage over 5-ASA and indomethacin in treating ulcerative colitis and Crohn's disease.

N-(2'-Hydroxyphenyl)-2-Propylpentanamide (HO-AAVPA) Inhibits HDAC1 and Increases the Translocation of HMGB1 Levels in Human Cervical Cancer Cells.

N-(2'-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) is a VPA derivative designed to be a histone deacetylase (HDAC) inhibitor. HO-AAVPA has better antiproliferative effect than VPA in cancer cell lines. Therefore, in this work, the inhibitory effect of HO-AAVPA on HDAC1, HDAC6, and HDAC8 was determined by in silico and in vitro enzymatic assay. Furthermore, its antiproliferative effect on the cervical cancer cell line (SiHa) and the translocation of HMGB1 and ROS production were evaluated. The results showed that HO-AAVPA inhibits HDAC1, which could be related with HMGB1 translocation from the nucleus to the cytoplasm due to HDAC1 being involved in the deacetylation of HMGB1. Furthermore, an increase in ROS production was observed after the treatment with HO-AAVPA, which also could contribute to HMGB1 translocation. Therefore, the results suggest that one of the possible antiproliferative mechanisms of HO-AAVPA is by HDAC1 inhibition which entails HMGB1 translocation and ROS increased levels that could trigger the cell apoptosis.

Tert-butyl-(4-hydroxy-3-((3-(2-methylpiperidin-yl)propyl)carbamoyl)phenyl)carbamate Has Moderated Protective Activity in Astrocytes Stimulated with Amyloid Beta 1-42 and in a Scopolamine Model.

Alzheimer's disease (AD) is a neurodegenerative disease with no cure nowadays; there is no treatment either to prevent or to stop its progression. In vitro studies suggested that tert-butyl-(4-hydroxy-3-((3-(2-methylpiperidin-yl)propyl)carbamoyl)phenyl) carbamate named the M4 compound can act as both ß-secretase and an acetylcholinesterase inhibitor, preventing the amyloid beta peptide (Aß) aggregation and the formation of fibrils (fAß) from Aß1-42. This work first aimed to assess in in vitro studies to see whether the death of astrocyte cells promoted by Aß1-42 could be prevented. Second, our work investigated the ability of the M4 compound to inhibit amyloidogenesis using an in vivo model after scopolamine administration. The results showed that M4 possesses a moderate protective effect in astrocytes against Aß1-42 due to a reduction in the TNF-α and free radicals observed in cell cultures. In the in vivo studies, however, no significant effect of M4 was observed in comparison with a galantamine model employed in rats, in which case this outcome was attributed to the bioavailability of M4 in the brain of the rats.

Recent Advances by In Silico and In Vitro Studies of Amyloid-ß 1-42 Fibril Depicted a S-Shape Conformation.

The amyloid-ß 1-42 (Aß1-42) peptide is produced by proteolytic cleavage of the amyloid precursor protein (APP) by sequential reactions that are catalyzed by γ and ß secretases. Aß1-42, together with the Tau protein are two principal hallmarks of Alzheimer's disease (AD) that are related to disease genesis and progression. Aß1-42 possesses a higher aggregation propensity, and it is able to form fibrils via nucleated fibril formation. To date, there are compounds available that prevent Aß1-42 aggregation, but none have been successful in clinical trials, possibly because the Aß1-42 structure and aggregation mechanisms are not thoroughly understood. New molecules have been designed, employing knowledge of the Aß1-42 structure and are based on preventing or breaking the ionic interactions that have been proposed for formation of the Aß1-42 fibril U-shaped structure. Recently, a new Aß1-42 fibril S-shaped structure was reported that, together with its aggregation and catalytic properties, could be helpful in the design of new inhibitor molecules. Therefore, in silico and in vitro methods have been employed to analyze the Aß1-42 fibril S-shaped structure and its aggregation to obtain more accurate Aß1-42 oligomerization data for the design and evaluation of new molecules that can prevent the fibrillation process.

In vitro effect of H2O 2, some transition metals and hydroxyl radical produced via fenton and fenton-like reactions, on the catalytic activity of AChE and the hydrolysis of ACh.

It is well known that the principal biomolecules involved in Alzheimer's disease (AD) are acetylcholinesterase (AChE), acetylcholine (ACh) and the amyloid beta peptide of 42 amino acid residues (Aß42). ACh plays an important role in human memory and learning, but it is susceptible to hydrolysis by AChE, while the aggregation of Aß42 forms oligomers and fibrils, which form senile plaques in the brain. The Aß42 oligomers are able to produce hydrogen peroxide (H2O2), which reacts with metals (Fe(2+), Cu(2+), Cr(3+), Zn(2+), and Cd(2+)) present at high concentrations in the brain of AD patients, generating the hydroxyl radical ((·)OH) via Fenton (FR) and Fenton-like (FLR) reactions. This mechanism generates high levels of free radicals and, hence, oxidative stress, which has been correlated with the generation and progression of AD. Therefore, we have studied in vitro how AChE catalytic activity and ACh levels are affected by the presence of metals (Fe(3+), Cu(2+), Cr(3+), Zn(2+), and Cd(2+)), H2O2 (without Aß42), and (·) OH radicals produced from FR and FLR. The results showed that the H2O2 and the metals do not modify the AChE catalytic activity, but the (·)OH radical causes a decrease in it. On the other hand, metals, H2O2 and (·)OH radicals, increase the ACh hydrolysis. This finding suggests that when H2O2, the metals and the (·)OH radicals are present, both, the AChE catalytic activity and ACh levels diminish. Furthermore, in the future it may be interesting to study whether these effects are observed when H2O2 is produced directly from Aß42.

Determining Structural Changes for Ligand Recognition between Human and Rat Phosphorylated BACE1 in Silico and Its Phosphorylation by GSK3ß at Thr252 by in Vitro Studies.

Alzheimer's disease (AD) is a neurodegenerative disease affecting older adults. AD pathogenesis involves the production of the highly neurotoxic amyloid-ß peptide 1-42 (Aß1-42) from ß-site amyloid precursor protein cleaving enzyme 1 (BACE1). The phosphorylation of BACE1 at Thr252 increases its enzymatic activity. This study examined the phosphorylation of BACE1 from human and rat BACE1 in silico through phosphorylation predictors. Besides, we explored how phosphorylation at various sites affected the BACE1 structure and its affinity with amyloid precursor protein (APP) and six BACE1 inhibitors. Additionally, we evaluated the phosphorylation of Thr252-BACE1 by glycogen synthase kinase 3 ß (GSK3ß) in vitro. The phosphorylation predictors showed that Thr252, Ser59, Tyr76, Ser71, and Ser83 could be phosphorylated. Also, Ser127 in rat BACE1 can be phosphorylated, but human BACE1 has a Gly at this position. Molecular dynamics simulations showed that Ser127 plays an important role in the open and closed BACE1 conformational structures. Docking studies and the molecular mechanics generalized Born surface area (MMGBSA) approach showed that human BACE1 phosphorylated at Thr252 and rat BACE1 phosphorylated at Ser71 have the best binding and free energy with APP, forming hydrogen bonds with Asp672. Importantly, inhibitors have a higher affinity for the phosphorylated rat BACE1 than for its human counterpart, which could explain their failure during clinical trials. Finally, in vitro experiments showed that GSK3ß could phosphorylate BACE1. In conclusion, BACE1 phosphorylation influences the BACE1 conformation and its recognition of ligands and substrates. Thus, these features should be carefully considered in the design of BACE1 inhibitors.

Comparison of the effect of chronic cadmium exposure on the antioxidant defense systems of kidney and brain in rat.

Cadmium (Cd(2+)) produces toxic effects on various tissues as kidney and liver, so several studies have focused to explore the effect produced by different doses and exposure times of this metal. However, little has been reported about the effect that Cd(2+) shows in the brain in vivo. Hence, this study aimed at comparing the effect of chronic Cd(2+) exposure on antioxidant defense systems of kidney and brain in rats. Six groups of male rats were employed; five were administered for 45 days with different doses of cadmium chloride (0.187, 0.375, 0.562, 0.937 and 1.125 mg/kg; i.p.) and the other was used as control. Free radicals (FRs) were directly quantified by electron paramagnetic resonance (EPR) spectroscopy; malondialdehyde (MDA), reduced glutathione (GSH) and the activity expression of superoxide dismutase (SOD2) and catalase (CAT) were also measured. The EPR results showed that there was no increase in FR content in kidney or brain. MDA and GSH levels increased in kidney but not in the brain. The SOD2 activity was not altered, but its expression decreased in both tissues. On the other hand, CAT activity and expression tended to increase at low doses and decrease at high doses in both tissues. Therefore, these results suggest that there exist compensatory mechanisms in both kidney and brain that are capable of avoiding the toxic effects exerted by Cd(2+) at these doses and exposure time.

Cytotoxic evaluation of YSL-109 in a triple negative breast cancer cell line and toxicological evaluations.

Breast cancer (BC) is the leading cause of cancer-related death in women worldwide. Triple negative breast cancer (TNBC) is the most aggressive form of BC being with the worst prognosis and the worst survival rates. There is no specific pharmacological target for the treatment of TNBC; conventional therapy includes the use of non-specific chemotherapy that generally has a poor prognosis. Therefore, the search of effective therapies against to TNBC continues at both preclinical and clinical level. In this sense, the exploration of different pharmacological targets is a continue task that pave the way to epigenetic modulation using novel small molecules. Lately, the inhibition of histone deacetylases (HDACs) has been explored to treat different BC, including TNBC. HDACs remove the acetyl groups from the ɛ-amino lysine resides on histone and non-histone proteins. In particular, the inhibition of HDAC6 has been suggested to be useful for the treatment of TNBC due to it is overexpressed in TNBC. Therefore, in this work, an HDAC6 selective inhibitor, the (S)-4-butyl-N-(1-(hydroxyamino)-3-(naphthalen-1-yl)-1-oxopropan-2-yl) benzamide (YSL-109), was assayed on TNBC cell line (MDA-MB231) showing an antiproliferative activity (IC50 = 50.34 ± 1.11 µM), whereas on fibroblast, it was lesser toxic. After corroborating the in vitro antiproliferative activity of YSL-109 in TNBC, the toxicological profile was explored using combined approach with in silico tools and experimental assays. YSL-109 shows moderate mutagenic activity on TA-98 strain at 30 and 100 µM in the Ames test, whereas YSL-109 did not show in vivo genotoxicity and its oral acute toxicity (LD50) in CD-1 female mice was higher than 2000 mg/kg, which is in agreement with our in silico predictions. According to these results, YSL-109 represents an interesting compound to be explored for the treatment of TNBC under preclinical in vivo models.

Molecular dynamics simulations depict structural motions of the whole human aryl hydrocarbon receptor influencing its binding of ligands and HSP90.

The aryl hydrocarbon receptor (AhR) has broad biological functions when its ligands activate it; the non-binding interactions with AhR have not been fully elucidated due to the absence of a complete tridimensional (3D) structure. Therefore, utilization of the whole 3D structure from Homo sapiens AhR by in silico studies will allow us to better study and analyze the binding mode of its full and partial agonists, and antagonists, as well as its interaction with the HSP90 chaperone. The 3D AhR structure was obtained from I-TASSER and subjected to molecular dynamics (MD) simulations to obtain different structural conformations and determine the most populated AhR conformer by clustering analyses. The AhR-3D structures selected from MD simulations and those from clustering analyses were used to achieve docking studies with some of its ligands and protein-protein docking with HSP90. Once the AhR-3D structure was built, its Ramachandran maps and energy showed a well-qualified 3D model. MD simulations showed that the per-Arnt-Sim homology (PAS) PAS A, PAS B, and Q domains underwent conformational changes, identifying the conformation when agonists were binding also, and HSP90 was binding near the PAS A, PAS B, and Q domains. However, when antagonists are binding, HSP90 does not bind near the PAS A, PAS B, and Q domains. These studies show that the complex agonist-AhR-HSP90 can be formed, but this complex is not formed when an antagonist is binding. Knowing the conformations when the ligands bind to AHR and the behavior of HSP90 allows for an understanding of its activity.Communicated by Ramaswamy H. Sarma.

LDH-A Promotes Metabolic Rewiring in Leucocytes from the Intestine of Rats Treated with TNBS.

Although the aetiology of inflammatory bowel diseases (IBDs) is still unknown, one of their main characteristics is that the immune system chronically affects the permeability of the intestinal lamina propria, in turn altering the composition of the microbiota. In this study, the TNBS rat model of colitis was used because it contains a complex inflammatory milieu of polymorphonuclear cells (PMN) and lymphocytes infiltrating the lamina propria. The aim of the present study was to investigate six dehydrogenases and their respective adaptations in the tissue microenvironment by quantifying enzymatic activities measured under substrate saturation conditions in epithelial cells and leukocytes from the lamina propria of rats exposed to TNBS. Our results show that in the TNBS group, an increased DAI score was observed due to the presence of haemorrhagic and necrotic areas in the colon. In addition, the activities of G6PDH and GADH enzymes were significantly decreased in the epithelium in contrast to the increased activity of these enzymes and increased lactate mediated by the LDH-A enzyme in leukocytes in the lamina propria of the colon. Over the past years, evidence has emerged illustrating how metabolism supports aspect of cellular function and how a metabolic reprogramming can drive cell differentiation and fate. Our findings show a metabolic reprogramming in colonic lamina propria leukocytes that could be supported by increased superoxide anion.

PAMAM-G4 protect the N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) and maintain its antiproliferative effects on MCF-7.

Our work group designed and synthesized a promissory compound N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA). The HO-AAVPA is a HDAC1 inhibitor and antiproliferative in cancer cell lines. However, HO-AAVPA is poor water solubility and enzymatically metabolized. In this work, the fourth-generation poly(amidoamine) dendrimer (PAMAM-G4) was used as a drug deliver carrier of HO-AAVPA. Moreover, HO-AAVPA and HO-AAVPA-PAMAM complex were submitted to forced degradation studies (heat, acid, base, oxidation and sunlight). Also, the HO-AAVPA-PAMAM-G4 complex was assayed as antiproliferative in a breast cancer cell line (MCF-7). The HO-AAVPA-PAMAM-G4 complex was obtained by docking and experimentally using three pH conditions: acid (pH = 3.0), neutral (pH = 7.0) and basic (pH = 9.0) showing that PAMAM-G4 captureand protect the HO-AAVPA from forced degradation, it is due to sunlight yielded a by-product from HO-AAVPA. In addition, the PAMAM-G4 favored the HO-AAVPA water solubility under basic and neutral pH conditions with significant difference (F(2,18) = 259.9, p < 0.001) between the slopes of the three conditions being the basic condition which solubilizes the greatest amount of HO-AAVPA. Finally, the HO-AAVPA-PAMAM-G4 complex showed better antiproliferative effects on MCF-7 (IC50 = 75.3 µM) than HO-AAVPA (IC50 = 192 µM). These results evidence that PAMAM-G4 complex improve the biological effects of HO-AAVPA.

In silico design of HDAC6 inhibitors with neuroprotective effects.

HDAC6 has emerged as a molecular target to treat neurodegenerative disorders, due to its participation in protein aggregate degradation, oxidative stress process, mitochondrial transport, and axonal transport. Thus, in this work we have designed a set of 485 compounds with hydroxamic and bulky-hydrophobic moieties that may function as HDAC6 inhibitors with a neuroprotective effect. These compounds were filtered by their predicted ADMET properties and their affinity to HDAC6 demonstrated by molecular docking and molecular dynamics simulations. The combination of in silico with in vitro neuroprotective results allowed the identification of a lead compound (FH-27) which shows neuroprotective effect that could be due to HDAC6 inhibition. Further, FH-27 chemical moiety was used to design a second series of compounds improving the neuroprotective effect from 2- to 10-fold higher (YSL-99, YSL-109, YSL-112, YSL-116 and YSL-121; 1.25 ± 0.67, 1.82 ± 1.06, 7.52 ± 1.78, 5.59 and 5.62 ± 0.31 µM, respectively). In addition, the R enantiomer of FH-27 (YSL-106) was synthesized, showing a better neuroprotective effect (1.27 ± 0.60 µM). In conclusion, we accomplish the in silico design, synthesis, and biological evaluation of hydroxamic acid derivatives with neuroprotective effect as suggested by an in vitro model. Communicated by Ramaswamy H. Sarma.

New compounds from heterocyclic amines scaffold with multitarget inhibitory activity on Aß aggregation, AChE, and BACE1 in the Alzheimer disease.

The preset neurodegenerations in Alzheimer disease (AD) are due to several mechanisms such as amyloidogenic proteolysis, neuroinflammation, mitochondrial dysfunction, neurofibrillary tangles, cholinergic dysfunction, among others. The aim of this work was to develop multitarget molecules for the treatment of AD. Therefore, a family of 64 molecules was designed based on ligand structure pharmacophores able to inhibit the activity of beta secretase (BACE1) and acetylcholinesterase (AChE) as well as to avoid amyloid beta (Aß1-42) oligomerization. The backbone of designed molecules consisted of a trisubstituted aromatic ring, one of the substituents was a heterocyclic amine (piperidine, morpholine, pyrrolidine or N-methyl pyrrolidine) separated from the aromatic system by three carbon atoms. The set of compounds was screened in silico employing molecular docking calculations and chemoinformatic analyses. Based on Gibbs free energy of binding, binding mode and in silico predicted toxicity results, three of the best candidates were selected, synthesized, and evaluated in vitro; F3S4-m, F2S4-m, and F2S4-p. All three compounds prevented Aß1-42 aggregation (F3S4-m in 30.5%, F2S4-p in 42.1%, and F2S4-m in 60.9%). Additionally, inhibitory activity against AChE (ki 0.40 µM and 0.19 µM) and BACE1 (IC50 15.97 µM and 8.38 µM) was also observed for compounds F2S4-m and F3S4-m, respectively. Despite the BACE IC50 results demonstrated that all compounds are very less potent respect to peptidomimetic inhibitor (PI-IV IC50 3.20 nM), we can still say that F3S4-m is capable to inhibit AChE and BACE1.