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(Thio)ureas ((T)Us) and benzothiazoles (BTs) each have demonstrated to have a great variety of biological activities. When these groups come together, the 2-(thio)ureabenzothizoles [(T)UBTs] are formed, improving the physicochemical as well as the biological properties, making these compounds very interesting in medicinal chemistry. Frentizole, bentaluron and methabenzthiazuron are examples of UBTs used for treatment of rheumatoid arthritis and as wood preservatives and herbicides in winter corn crops, respectively. With this antecedent, we recently reported a bibliographic review about the synthesis of this class of compounds, from the reaction of substituted 2-aminobenzothiazoles (ABTs) with iso(thio)cyanates, (thio)phosgenes, (thio)carbamoyl chlorides, 1,1'-(thio)carbonyldiimidazoles, and carbon disulfide. Herein, we prepared a bibliographic review about those features of design, chemical synthesis, and biological activities relating to (T)UBTs as potential therapeutic agents. This review is about synthetic methodologies generated from 1968 to the present day, highlighting the focus to transform (T)UBTs to compounds containing a range substituents, as illustrated with 37 schemes and 11 figures and concluded with 148 references. In this topic, the scientists dedicated to medicinal chemistry and pharmaceutical industry will find useful information for the design and synthesis of this interesting group of compounds with the aim of repurposing these compounds. [ABSTRACT FROM AUTHOR]

Preclinical and clinical evidence supports melatonin and its analogues as potential treatment for diseases involving cognitive deficit such as Alzheimer's disease. In this work, we evaluated by in silico studies a set of boron-containing melatonin analogues on MT1 and MT2 receptors. Then, we synthesized a compound (borolatonin) identified as potent agonist. After chemical characterization, its evaluation in a rat model with cognitive deficit showed that it induced ameliorative effects such as those induced by equimolar administration of melatonin in behavioral tests and in neuronal immunohistochemistry assays. Our results suggest the observed effects are by means of action on the melatonin system. Further studies are required to clarify the mechanism(s) of action, as the beneficial effects on disturbed memory by gonadectomy in male rats are attractive. [ABSTRACT FROM AUTHOR]

Molecules of 1,2-bis(4-bromophenyl)-1H-benzimidazole, C19-H12Br2N2, (I), and 2-(4-bromophenyl)-1-(4-nitrophenyl)-1H-benzimidazole, C19H12BrN3O2, (II), are arranged in dimeric units through C—H...N and parallel-displaced π-stacking interactions favoured by the appropriate disposition of N- and C-bonded phenyl rings with respect to the mean benzimidazole plane. The molecular packing of the dimers of (I) and (II) arises by the concurrence of a diverse set of weak intermolecular C—X...D (X = H, NO2; D = O, π) interactions. [ABSTRACT FROM AUTHOR]

Abstract: Since many drugs are metabolized by cytochrome P450 (CYP450), biotransformation studies using these enzymes are valuable in drug development. In this work, the biotransformation by CYP1A1 and CYP2B1 of two acetylcholinesterase (AChE) inhibitors, 4-(4′-hydroxy-phenylamino)-4-oxo propanoic acid (A) and 1H-pyrrolidine-1-(4′-hydroxy-phenyl)-2,5-dione (B), was investigated through docking and molecular dynamics (MD) simulations and by experimental methods using rat liver microsomes pretreated with β-naphthoflavone and phenobarbital (CYP1A1 and CYP2B1 inducers, respectively). The target proteins were initially built by homology modeling, and the resulting three-dimensional structures were refined by MD to obtain fifteen snapshots of each P450 isoform. These snapshots were used to dock compounds A and B as well as the reference compound acetaminophen (APAP). We confirmed that APAP produces a toxic intermediate (N-acetyl-p-benzoquinone imine) upon interaction of its amide group with the heme iron of CYP1A1. However, neither A nor B presented this kind of interaction within any snapshot with CYP1A1. On the other hand, when APAP, A and B were docked on CYP2B1, their hydroxyl group was located near the heme iron on the snapshot at 3.5 ns. Furthermore, B maintained the same position on all snapshots of this isoform. Therefore, theoretical results suggests that A and B do not generate toxic metabolites. These data were supported by HPLC analysis showing only one metabolite from A and B, which was identified by GC-MS as the hydroxylated product. Altogether, our results suggest that neither test compound is toxic. [ABSTRACT FROM AUTHOR]

Benzimidazole is an important heterocyclic fragment, present in many biologically active compounds with a great variety of therapeutic purposes. Most of the benzimidazole activities are explained through the existence of 1,3-tautomeric equilibrium. As the binding affinity of each tautomer to a protein target depends on an established bioactive conformation, the effect of tautomers on the ligand protein binding mechanism is determinant. In this work, we searched and analyzed a series of reported 13C-NMR spectra of benzazoles and benzazolidine-2-thiones with the purpose of estimating their tautomeric equilibrium. Herein, several approaches to determine this problem are presented, which makes it a good initial introduction to the non-expert reader. This chemical shift difference and C4/C7 signals of benzimidazolidine-2-thione and 1-methyl-2-thiomethylbenzimidazole as references were used in this work to quantitatively calculate, in solution, the pyrrole–pyridine tautomeric ratio in equilibrium. The analysis will help researchers to correctly assign the chemical shifts of benzimidazoles and to calculate their intracyclic or exocyclic tautomeric ratio as well as mesomeric proportion in benzimidazoles. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most frequently diagnosed cancer and is the second-most common cause of death in women worldwide. Because of this, the search for new drugs and targeted therapy to treat BC is an urgent and global need. Histone deacetylase 6 (HDAC6) is a promising anti-BC drug target associated with its development and progression. In the present work, the design and synthesis of a new family of dihydropyrazole-carbohydrazide derivatives (DPCH) derivatives focused on HDAC6 inhibitory activity is presented. Computational chemistry approaches were employed to rationalize the design and evaluate their physicochemical and toxic-biological properties. The new family of nine DPCH was synthesized and characterized. Compounds exhibited optimal physicochemical and toxicobiological properties for potential application as drugs to be used in humans. The in silico studies showed that compounds with –Br, –Cl, and –OH substituents had good affinity with the catalytic domain 2 of HDAC6 like the reference compounds. Nine DPCH derivatives were assayed on MCF-7 and MDA-MB-231 BC cell lines, showing antiproliferative activity with IC50 at μM range. Compound 2b showed, in vitro, an IC50 value of 12 ± 3 µM on human HDAC6. The antioxidant activity of DPCH derivatives showed that all the compounds exhibit antioxidant activity similar to that of ascorbic acid. In conclusion, the DPCH derivatives are promising drugs with therapeutic potential for the epigenetic treatment of BC, with low cytotoxicity towards healthy cells and important antioxidant activity. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The aqueous extract of O. rosea protected the TNBS-induced colonic damage in rats. • The aqueous extract of O. rosea down-regulated the MPO activity. • Isolimonic acid was able to bind the MPO with high affinity. • Polyphenolic compounds, alkaloids, and terpenes were characterized from O. rosea. Abstract Oenothera rosea L´Hér. ex Ait is a species traditionally used in the treatment of inflammation, headache, stomach pain, infections, among others. The aim of this study was evaluating the acute anti-inflammatory activity of the aqueous extract of O. rosea by 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Rats were randomized into six groups: (I) Sham; (II) EtOH; (III) TNBS; and (IV–VI) 250, 500 and 750 mg/Kg, respectively. The colonic injury was induced (groups III–VI) by intrarectal instillation of 0.25 mL of TNBS (10 mg) in 50% ethanol. Groups I and II received an enema (0.25 mL) of physiological saline solution or 50% ethanol, respectively. Treatments were administered by oral gavage 48, 24 and 1 h prior, and 24 h after the induction. The inflammatory response was assessed considering the macroscopic and microscopic damage, the serum nitric oxide (NO), the colonic IL-1β levels, and the myeloperoxidase (MPO) activity. Moreover, we performed an LC–MS-based metabolite profiling, and a docking on the MPO. Doses of 500 and 750 mg/Kg showed a protective effect in the TNBS-induced colonic damage. This activity was related to the downregulation of evaluated parameters. Also, considering previous reports, 29 metabolites of 91 detected were selected for the docking, of which Isolimonic acid (29) and Kaempferol 3-(2′′,4′′-diacetylrhamnoside) (10) showed the highest affinity to MPO. The aqueous extract of O. rosea protected the TNBS-induced colonic damage in rats, an effect that could be associated with the presence of polyphenolic compounds, alkaloids, and terpenes; as well as their ability to down-regulate MPO activity. [ABSTRACT FROM AUTHOR]

Prostate cancer remains one of the leading health issues without a fully effective treatment. Medicinal plants are one of the primary sources of compounds for treating numerous ailments. In this sense, the Oenothera genus contains metabolites with antiproliferative activity on cancer cells. For this, the study aimed to explore the antiproliferative activity of its extracts against prostate cancer and identify its metabolites (under metabolomics analyses) associated with anticancer and/or antiproliferative properties. For this reason, a LC-MS/MS-based metabolomic analysis was performed to demonstrate the possible metabolites present in O. rosea. In addition, the antiproliferative activity of different extracts in the human prostate cancer cell line DU145 was evaluated. All extracts have antiproliferative effects on DU145 cells at 72 h, with moderate activity being the best ethanolic either 48 or 72 h. Finally, by LC-MS/MS-based metabolomics, 307 compounds from aqueous, methanolic, ethanolic, and ethyl acetate extracts from which 40 putative metabolites identified were organized as anti-inflammatory, anticancer, and/or antiproliferative activities according to previously reported. These results provide evidence that O. rosea could be used as an antiproliferative agent due to its chemical contents used as polypharmacy with low concentration levels. [Display omitted] • The metabolomic profile of Oenothera rosea extracts evidenced 307 metabolites. • O. rosea contains 40 metabolites with anticancer and/or antiproliferative properties. • Oenothera rosea has a potential anticancer and antiproliferative activity. • Ethanol extract of Oenothera rosea showed the highest anticancer activity. [ABSTRACT FROM AUTHOR]

Inhibition of β-site amyloid–β-protein precursor cleaving enzyme 1 (BACE1) represents a promising approach for the treatment of Alzheimer's disease (AD). However, the development of a selective BACE1 inhibitor is difficult due to its highly flexible catalytic site and homology to other aspartic proteases, including BACE2 and Cathepsin D (CTSD). Aiming to better understand the structural factors responsible for selective BACE1 inhibition, we performed alignment studies, molecular dynamics (MD) simulations and docking studies to explore the recognition of four selective BACE1 inhibitors by aspartyl proteases. The results show that selective BACE1 inhibition may be due to the formation of strong electrostatic interactions with Asp32 and Asp228 and a large number of hydrogen bonds, π-π and Van der Waals interactions with the amino acid residues located inside the catalytic cavity, which has different volume and shape compared to BACE2 and CTSD. Hindrance effects avoid the accommodation of ligands in the small catalytic site of BACE2, resulting in a lower affinity and the high cavity of CTSD results in the formation of a small number of interactions with the ligands, although they show a similar binding mode with BACE1. These results might help to rationalize the design of selective BACE1 inhibitors. [ABSTRACT FROM AUTHOR]

Among the multiple factors that induce Alzheimer’s disease, aggregation of the amyloid β peptide (Aβ) is considered the most important due to the ability of the 42-amino acid Aβ peptides (Aβ1–42) to form oligomers and fibrils, which constitute Aβ pathological aggregates. For this reason, the development of inhibitors of Aβ1–42 pathological aggregation represents a field of research interest. Several Aβ1–42 fibrillization inhibitors possess tertiary amine and aromatic moieties. In the present study, we selected 26 compounds containing tertiary amine and aromatic moieties with or without substituents and performed theoretical studies that allowed us to select four compounds according to their free energy values for Aβ1–42 in α-helix (Aβ-α), random coil (Aβ-RC) and β-sheet (Aβ-β) conformations. Docking studies revealed that compound 5 had a higher affinity for Aβ-α and Aβ-RC than the other compounds. In vitro, this compound was able to abolish Thioflavin T fluorescence and favored an RC conformation of Aβ1–42 in circular dichroism studies, resulting in the formation of amorphous aggregates as shown by atomic force microscopy. The results obtained from quantum studies allowed us to identify a possible pharmacophore that can be used to design Aβ1–42 aggregation inhibitors. In conclusion, compounds with higher affinity for Aβ-α and Aβ-RC prevented the formation of oligomeric species. [ABSTRACT FROM AUTHOR]

It is well known that CR (caloric restriction) reduces oxidative damage to proteins, lipids and DNA, although the underlying mechanism is unclear. However, information concerning the effect of CR on the host response to infection is sparse. In this study, 6-month-old mice that were fed AL (ad libitum) or with a CR diet were infected with Salmonella serovar Typhimurium. EPR (electron paramagnetic resonance; also known as ESR (electron spin resonance)) was used to identify FRs (free radicals). These results were subsequently correlated with SOD (superoxide dismutase) catalytic activity, iNOS [inducible NOS (nitric oxide synthase) or NOSII] expression and NO (nitric oxide) content. EPR analysis of liver samples demonstrated that there was a higher quantity of FRs and iron-nitrosyl complex in infected mice provided with a CR diet as compared with those on an AL diet, indicating that CR was beneficial by increasing the host response to Salmonella Typhimurium. Furthermore, in infected mice on the CR diet, NOSII expression was higher, NO content was greater and spleen colonization was lower, compared with mice on the AL diet. No changes in SOD activity were detected, indicating that the NO produced participated more in the formation of iron-nitrosyl complexes than peroxynitrite. These results suggest that CR exerts a protective effect against Salmonella Typhimurium infection by increasing NO production [ABSTRACT FROM AUTHOR]

Being the base of several non-communicable diseases, including cancer, inflammation is a complex process generated by tissue damage or change in the body homeostatic state. Currently, the therapeutic treatment for chronic inflammation related diseases is based on the use of selective cyclooxygenase II enzyme, COX-2, inhibitors or Coxibs, which have recently regained attention giving their preventive role in colon cancer. Thus, the discovery of new molecules that selectively inhibit COX-2 and other inflammatory mediators is a current challenge in the medicinal chemistry field. 1-Phenylbenzimidazoles have shown potential COX inhibitory activity, because they can reproduce the interaction profile of known COX inhibitors. Therefore, in the present investigation a series of 1,2-diphenylbenzimidazoles (DPBI) with different aromatic substitutions in the para position were synthesized and their interaction with COX-2 and nitric oxide synthase, iNOS, was determined in silico, in vitro and in vivo. Compound 2-(4-bromophenyl)-1-(4-nitrophenyl)-1 H -benzo[ d ]imidazole showed the best inhibition towards COX-2, while compounds N -(4-(2-(4-bromophenyl)-1 H -benzo[ d ]imidazol-1-yl)phenyl)acetamide and N -(4-(2-(4-chlorophenyl)-1 H -benzo[ d ]imidazol-1-yl)phenyl)acetamide diminished the production of NO in vitro. Additionally, they had a significant anti-inflammatory activity in vivo when given orally. [ABSTRACT FROM AUTHOR]