Synthesis, biological evaluation and molecular modeling studies of novel 1,2,3-triazole-linked menadione-furan derivatives as P2X7 inhibitors.

The P2X7 receptor (P2X7R) is an ion channel that promotes the passage of ions through the membrane through brief stimulation once activated by ATP, its endogenous opener. However, prolonged stimulation with ATP, which occurs in pathological processes, opens a nonselective pore in the plasma membrane, allowing the passage of large molecules and leading to cytokine release or even cell death. In this sense, the search for new inhibitors for this receptor has attracted a great deal of attention in recent years. Considering the booming of biomass upgrading reactions in recent years and the continued efforts to synthesize biologically active molecules containing the 1,2,3-triazole ring, in the present work, we aimed to investigate whether triazole-linked menadione-furan derivatives could present P2X7R inhibitory activity. The novel compounds were tested for their inhibitory activity on ATP-induced dye uptake in peritoneal macrophages. Some have shown promising results, having displayed IC50 values lower than that of the P2X7R inhibitor BBG. Molecular docking studies also indicated that the active compounds bind to an allosteric site on P2X7R, presenting potential P2X7R inhibition.

Pro-Apoptotic Antitumoral Effect of Novel Acridine-Core Naphthoquinone Compounds against Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a global public health problem with high incidence and mortality. The chemotherapeutic agents used in the clinic, alone or in combination, usually lead to important side effects. Thus, the discovery and development of new antineoplastic drugs are essential to improve disease prognosis and reduce toxicity. In the present study, acridine-core naphthoquinone compounds were synthesized and evaluated for their antitumor activity in OSCC cells. The mechanism of action, pharmacokinetics, and toxicity parameters of the most promising compound was further analyzed using in silico, in vitro, and in vivo methods. Among the derivatives, compound 4e was highly cytotoxic (29.99 µM) and selective (SI 2.9) at levels comparable and generally superior to chemotherapeutic controls. Besides, compound 4e proved to be non-hemolytic, stable, and well tolerated in animals at all doses tested. Mechanistically, compound 4e promoted cell death by apoptosis in the OSCC cell, and molecular docking studies suggested this compound possibly targets enzymes important for tumor progression, such as RSK2, PKM2, and topoisomerase IIα. Importantly, compound 4e presented a pharmacological profile within desirable parameters for drug development, showing promise for future preclinical trials.

Menadione: a platform and a target to valuable compounds synthesis.

Naphthoquinones are important natural or synthetic compounds belonging to the general class of quinones. Many compounds in this class have become drugs that are on the pharmaceutical market for the treatment of various diseases. A special naphthoquinone derivative is menadione, a synthetic naphthoquinone belonging to the vitamin K group. This compound can be synthesized by different methods and it has a broad range of biological and synthetic applications, which will be highlighted in this review.

Synthesis and in vitro and in silico studies of 1H- and 2H-1,2,3-triazoles as antichagasic agents.

1,2,3-triazole heterocycles stand out in medicinal chemistry for having great structural diversity and bioactivities. In this study, two series of triazoles were synthesized. One was obtained by the 1,3-dipolar cycloaddition reaction between ethyl cyanoacetate and several phenyl azides forming 1H-1,2,3-triazoles and the other by rearrangement of Dimroth forming and 2H-1,2,3-triazoles. Both series were shown to be active against the epimastigote form of Trypanosoma cruzi. The 1,2,3-triazoles 16d (S.I. between 100 and 200), 17d and 16f (S.I. > 200) were the most active compounds and capable of breaking the plasma membrane of trypomastigotes acting on CYP51 and inhibiting ergosterol synthesis. Candidate 16d exhibited the best and most favorable profile when interacting with CYP51.

Drug repurposing for the treatment of COVID-19: Pharmacological aspects and synthetic approaches.

In December 2019, a new variant of SARS-CoV emerged, the so-called acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus causes the new coronavirus disease (COVID-19) and has been plaguing the world owing to its unprecedented spread efficiency, which has resulted in a huge death toll. In this sense, the repositioning of approved drugs is the fastest way to an effective response to a pandemic outbreak of this scale. Considering these facts, in this review we provide a comprehensive and critical discussion on the chemical aspects surrounding the drugs currently being studied as candidates for COVID-19 therapy. We intend to provide the general chemical community with an overview on the synthetic/biosynthetic pathways related to such molecules, as well as their mechanisms of action against the evaluated viruses and some insights on the pharmacological interactions involved in each case. Overall, the review aims to present the chemical aspects of the main bioactive molecules being considered to be repositioned for effective treatment of COVID-19 in all phases, from the mildest to the most severe.

Novel VEGFR-2 inhibitors with an N-acylhydrazone scaffold.

Vascular endothelial growth factor receptor 2 (VEGFR-2) is a tyrosine kinase that mediates a large number of cell responses associated with angiogenesis. The control of the angiogenic pathway in tumorigenesis by the inhibition of VEGFR-2 is considered a promising therapeutic strategy for the prevention and control of solid tumor growth. In this study, the design, synthesis, and biological evaluation of a novel series of VEGFR-2 inhibitors with an N-acylhydrazone (NAH) scaffold (9a-h) are reported. The molecular design is validated by docking studies and by in vitro inhibitory activity assays. Compounds 9b, 9c, 9d, and 9f effectively inhibited neovascularization induced by VEGF in the chorioallantoic membrane assay. Thus, these NAH derivatives are promising antiangiogenic prototypes.

Antiproliferative Activity of N-Acylhydrazone Derivative on Hepatocellular Carcinoma Cells Involves Transcriptional Regulation of Genes Required for G2/M Transition.

Liver cancer is the second leading cause of cancer-related death in males. It is estimated that approximately one million deaths will occur by 2030 due to hepatic cancer. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer subtype and is commonly diagnosed at an advanced stage. The drug arsenal used in systemic therapy for HCC is very limited. Multikinase inhibitors sorafenib (Nexavar®) and lenvatinib (Lenvima®) have been used as first-line drugs with modest therapeutic effects. In this scenario, it is imperative to search for new therapeutic strategies for HCC. Herein, the antiproliferative activity of N-acylhydrazone derivatives was evaluated on HCC cells (HepG2 and Hep3B), which were chemically planned on the ALL-993 scaffold, a potent inhibitor of vascular endothelial growth factor 2 (VEGFR2). The substances efficiently reduced the viability of HCC cells, and the LASSBio-2052 derivative was the most effective. Further, we demonstrated that LASSBio-2052 treatment induced FOXM1 downregulation, which compromises the transcriptional activation of genes required for G2/M transition, such as AURKA and AURKB, PLK1, and CDK1. In addition, LASSBio-2052 significantly reduced CCNB1 and CCND1 expression in HCC cells. Our findings indicate that LASSBio-2052 is a promising prototype for further in vivo studies.

Exploring the Antimicrobial and Antitumoral Activities of Naphthoquinone-Grafted Chitosans.

Biopolymers obtained from natural macromolecules are noteworthy among materials presenting high biocompatibility and adequate biodegradability, as is the case of chitosan (CS), making this biopolymeric compound a suitable drug delivery system. Herein, chemically-modified CS were synthetized using 2,3-dichloro-1,4-naphthoquinone (1,4-NQ) and the sodium salt of 1,2-naphthoquinone-4-sulfonic acid (1,2-NQ), producing 1,4-NQ-CS and 1,2-NQ-CS by three different methods, employing an ethanol and water mixture (EtOH:H2O), EtOH:H2O plus triethylamine and dimethylformamide. The highest substitution degree (SD) of 0.12 was achieved using water/ethanol and triethylamine as the base for 1,4-NQ-CS and 0.54 for 1,2-NQ-CS. All synthesized products were characterized by FTIR, elemental analysis, SEM, TGA, DSC, Raman, and solid-state NMR, confirming the CS modification with 1,4-NQ and 1,2-NQ. Chitosan grafting to 1,4-NQ displayed superior antimicrobial activities against Staphylococcus aureus and Staphylococcus epidermidis associated with improved cytotoxicity and efficacy, indicated by high therapeutic indices, ensuring safe application to human tissue. Although 1,4-NQ-CS inhibited the growth of human mammary adenocarcinoma cells (MDA-MB-231), it is accompanied by cytotoxicity and should be considered with caution. The findings reported herein emphasize that 1,4-NQ-grafted CS may be useful in protecting injured tissue against bacteria, commonly found in skin infections, until complete tissue recovery.

N-acylhydrazone derivative modulates cell cycle regulators promoting mitosis arrest and apoptosis in estrogen positive MCF-7 breast cancer cells.

Breast cancer is the leading cause of cancer death among women worldwide. About 75% of all diagnosed cases are hormone-positive, which are treated with hormone therapy. However, many patients are refractory or become resistant to the drugs used in therapeutic protocols. In this scenario, it is essential to identify new substances with pharmacological potential against breast cancer. VEGFR2 inhibitors are considered promising antitumor agents not only due to their antiangiogenic activity but also by inhibiting the proliferation of tumor cells. Thus, the present study aimed to evaluate the effects of N-acylhydrazone derivative LASSBio-2029 on the proliferative behavior of MCF-7 cells. We observed a promising antitumor potential of this substance due to its ability to modulate critical cell cycle regulators including mitotic kinases (CDK1, AURKA, AURKB, and PLK1) and CDK inhibitor (CDKN1A). Increased frequencies of abnormal mitosis and apoptotic cells were observed in response to treatment. A molecular docking analysis predicts that LASSBio-2029 could bind to the proto-oncoprotein ABL1, which participates in cell cycle control, interacting with other controller proteins and regulating centrosome-associated tubulins. Finally, we created a gene signature with the downregulated genes, whose reduced expression is associated with a higher relapse-free survival probability in breast cancer patients.

Microencapsulated and Ready-to-Eat Beetroot Soup: A Stable and Attractive Formulation Enriched in Nitrate, Betalains and Minerals.

Beetroot is a tuber rich in antioxidant compounds, i.e., betanin and saponins, and is one of the main sources of dietary nitrate. The aim of the present study was to microencapsulate a ready-to-eat beetroot soup by lyophilization using different encapsulating agents, which supply the required amount of bioactive nutrients. Particle size distributions ranged from 7.94 ± 1.74 to 245.66 ± 2.31 µm for beetroot soup in starch and from 30.56 ± 1.66 to 636.34 ± 2.04 µm in maltodextrin. Microparticle yields of powdered beetroot soup in starch varied from 77.68% to 88.91%, and in maltodextrin from 75.01% to 80.25%. The NO3- and total betalain contents at a 1:2 ratio were 10.46 ± 0.22 mmol·100 g-1 fresh weight basis and 219.7 ± 4.92 mg·g-1 in starch powdered beetroot soup and 8.43 ± 0.09 mmol·100 g-1 fresh weight basis and 223.9 ± 4.21 mg·g-1 in maltodextrin powdered beetroot soup. Six distinct minerals were identified and quantified in beetroot soups, namely Na, K, Mg, Mn, Zn and P. Beetroot soup microencapsulated in starch or maltodextrin complied with microbiological quality guidelines for consumption, with good acceptance and purchase intention throughout 90 days of storage. Microencapsulated beetroot soup may, thus, comprise a novel attractive strategy to offer high contents of bioaccessible dietary nitrate and antioxidant compounds that may aid in the improvement of vascular-protective effects.

Antimicrobial and wound healing potential of naphthoquinones encapsulated in nanochitosan.

Introduction: The use of chitosan in pharmaceutical formulations is an advantageous approach due to this compound intrinsic biodegradability and biocompatibility, as well as ready availability and low polymer cost. Methods: Herein, the naphthoquinones 3- chloromethylene-menadione (NQ1) and 2,3-dichloro-1,4-naphthoquinone (NQ2) were nanoencapsulated into chitosan (CNP) by the ionotropic gelatinization technique and characterized by DLS, FTIR, SEM, TGA and DSC, and their release profiles evaluated. The antimicrobial and wound healing activities were investigated. Results and Discussion: Homogeneous chitosan nanocapsulses of about 193 nm and Z potential ranging from +30.6 to +33.1 mV loaded with NQ1 (CNP-NQ1) or NQ2 (CNPQNQ2). With nanoencapsulation efficiencies of ≥ 96%, the solubility of naphthoquinones in aqueous environments was improved, making them suitable for biological system applications. The encapsulated naphthoquinones displayed a controlled release of approximately 80% for CNP-NQ1 and 90% for CNP-NQ2 over an 8 h period at 36°C. Both CNP-NQ1 and CNP-NQ2 retained the already established free naphthoquinone antimicrobial activity against two Staphylococcus aureus strains, Staphylococcus epidermidis, Streptococcus pyogenes and Pseudomonas aeruginosa. Although presenting low toxicity to healthy human cells, only CNP-NQ1 displayed therapeutic indices above 100 for S. aureus and S. epidermidis and above 27 for S. pyogenes and P. aeruginosa, allowing for safe use in human tissues. Furthermore, CNP-NQ1 did not impair the migration of human fibroblast cells in scratch assays, adding promising wound healing properties to this formulation. These findings emphasize that CNP-NQ1 may be useful in protecting injured skin tissue from bacterial contamination, avoiding skin infections not only by reducing bacterial loads but also by accelerating the healing process until complete dermal tissue recovery.

Recent Synthetic Approaches towards Small Molecule Reactivators of p53.

The tumor suppressor protein p53 is often called "the genome guardian" and controls the cell cycle and the integrity of DNA, as well as other important cellular functions. Its main function is to trigger the process of apoptosis in tumor cells, and approximately 50% of all cancers are related to the inactivation of the p53 protein through mutations in the TP53 gene. Due to the association of mutant p53 with cancer therapy resistance, different forms of restoration of p53 have been subject of intense research in recent years. In this sense, this review focus on the main currently adopted approaches for activation and reactivation of p53 tumor suppressor function, focusing on the synthetic approaches that are involved in the development and preparation of such small molecules.