Coumarin-Based Compounds as Inhibitors of Tyrosinase/Tyrosine Hydroxylase: Synthesis, Kinetic Studies, and In Silico Approaches.

Cancer represents the main cause of morbidity and mortality worldwide, constituting a serious health problem. In this context, melanoma represents the most aggressive and fatal type of skin cancer, with death rates increasing every year. Scientific efforts have been addressed to the development of inhibitors targeting the tyrosinase enzyme as potential anti-melanoma agents due to the importance of this enzyme in melanogenesis biosynthesis. Coumarin-based compounds have shown potential activity as anti-melanoma agents and tyrosinase inhibitors. In this study, coumarin-based derivatives were designed, synthesized, and experimentally evaluated upon tyrosinase. Compound FN-19, a coumarin-thiosemicarbazone analog, exhibited potent anti-tyrosinase activity, with an IC50 value of 42.16 ± 5.16 µM, being more active than ascorbic acid and kojic acid, both reference inhibitors. The kinetic study showed that FN-19 acts as a mixed inhibitor. Still, for this compound, molecular dynamics (MD) simulations were performed to determine the stability of the complex with tyrosinase, generating RMSD, RMSF, and interaction plots. Additionally, docking studies were performed to elucidate the binding pose at the tyrosinase, suggesting that the hydroxyl group of coumarin derivative performs coordinate bonds (bidentate) with the copper(II) ions at distances ranging from 2.09 to 2.61 Å. Then, MM/PBSA calculations revealed that van der Waals interactions are the most relevant intermolecular forces for complex stabilization. Furthermore, it was observed that FN-19 has a binding energy (ΔEMM) value similar to tropolone, a tyrosinase inhibitor. Therefore, the data obtained in this study will be useful for designing and developing novel coumarin-based analogs targeting the tyrosinase enzyme.

Computer-aided design of 1,4-naphthoquinone-based inhibitors targeting cruzain and rhodesain cysteine proteases.

Chagas disease and Human African Trypanosomiasis (HAT) are caused by Trypanosoma cruzi and T. brucei parasites, respectively. Cruzain (CRZ) and Rhodesain (RhD) are cysteine proteases that share 70% of identity and play vital functions in these parasites. These macromolecules represent promising targets for designing new inhibitors. In this context, 26 CRZ and 5 RhD 3D-structures were evaluated by molecular redocking to identify the most accurate one to be utilized as a target. Posteriorly, a virtual screening of a library containing 120 small natural and nature-based compounds was performed on both of them. In total, 14 naphthoquinone-based analogs were identified, synthesized, and biologically evaluated. In total, five compounds were active against RhD, being three of them also active on CRZ. A derivative of 1,4-naphthoquinonepyridin-2-ylsulfonamide was found to be the most active molecule, exhibiting IC50 values of 6.3 and 1.8 µM for CRZ and RhD, respectively. Dynamic simulations at 100 ns demonstrated good stability and do not alter the targets' structures. MM-PBSA calculations revealed that it presents a higher affinity for RhD (-25.3 Kcal mol-1) than CRZ, in which van der Waals interactions were more relevant. A mechanistic hypothesis (via C3-Michael-addition reaction) involving a covalent mode of inhibition for this compound towards RhD was investigated by covalent molecular docking and DFT B3LYP/6-31 + G* calculations, exhibiting a low activation energy (ΔG‡) and providing a stable product (ΔG), with values of 7.78 and - 39.72 Kcal mol-1, respectively; similar to data found in the literature. Nevertheless, a reversibility assay by dilution revealed that JN-11 is a time-dependent and reversible inhibitor. Finally, this study applies modern computer-aided techniques to identify promising inhibitors from a well-known chemical class of natural products. Then, this work could inspire other future studies in the field, being useful for designing potent naphthoquinones as RhD inhibitors.

Druggable targets from coronaviruses for designing new antiviral drugs.

Severe respiratory infections were highlighted in the SARS-CoV outbreak in 2002, as well as MERS-CoV, in 2012. Recently, the novel CoV (COVID-19) has led to severe respiratory damage to humans and deaths in Asia, Europe, and Americas, which allowed the WHO to declare the pandemic state. Notwithstanding all impacts caused by Coronaviruses, it is evident that the development of new antiviral agents is an unmet need. In this review, we provide a complete compilation of all potential antiviral agents targeting macromolecular structures from these Coronaviruses (Coronaviridae), providing a medicinal chemistry viewpoint that could be useful for designing new therapeutic agents.

Synthesis of newly functionalized 1,4-naphthoquinone derivatives and their effects on wound healing in alloxan-induced diabetic mice.

Naphthoquinone derivatives have various pharmacological properties. Here, we describe the synthesis of new 1,4-naphthoquinone derivatives inspired by lawsone and ß-lapachone and their effects on both migration of fibroblasts in vitro and dermal wound healing in diabetic mice. NMR and FTIR spectroscopy aided characterization of chemical composition and demonstrated the molecular variations after the synthesis of four different derivatives, namely 2-bromo-1,4-naphthoquinone (termed derivative S3), 2-N-phenylamino-1,4-naphthoquinone (derivative S5), 2-N-isonicotinoyl-hydrazide-1,4-naphthoquinone (derivative S6), and 1-N-isonicotinoyl-hydrazone-[2-hydroxy-3-(3-methyl-2-butenyl)]-1,4-naphthoquinone (derivative S7). Our results indicate that derivatives S3, S5, S6 and S7 were non-toxic to the 3T3 fibroblast cell line. In scratch assays, derivatives S3 and S6, but not S5 or S7, stimulated the migration of fibroblasts. Compared with untreated diabetic mice, S3, S6 and S7 treatments accelerated wound closure. However, derivative S3 was optimal for the stimulation of epithelization, thereby increasing the number of keratinocyte layers and blood vessels, and reducing diffuse cellular infiltration, compared to derivatives S6 and S7. Our results suggest that novel 1,4-naphthoquinone derivatives promote fibroblast migration and accelerate wound closure under diabetic conditions.

Thalidomide analogs from diamines: Synthesis and evaluation as inhibitors of TNF-alpha production.

Fourteen thalidomide analogs bearing two phthalimido units were prepared in high yields (83-94%) by condensation of different diamines with phthalic or 3-nitrophthalic anhydride. An in vitro investigation of the compounds as inhibitors of the TNF-alpha production was performed. The inhibition was higher for compounds bearing amino and nitro groups and was modulated by increasing the size of the spacers between the phthalimide groups.

Fluoroquinolones: an important class of antibiotics against tuberculosis.

Tuberculosis (TB) is a global health problem due to the lack of new drugs in the market and also due to the advent of multidrug resistant strains (MDR). This disease affects around 8 million people and kills almost 3 million people each year and it is estimated that there are 1 billion infected with TB worldwide. Due to this problem fluoroquinolones have attracted much attention as the new class of anti TB drugs due to their fewer toxic side effects, improved pharmacokinetic properties and extensive and potent activity against Gram-positive and Gram-negative bacteria, including resistant strains. In this present review we report fluoroquinolones as a promising new class of anti TB.

Papel dos aminoácidos excitatórios na reação de defesa integrada no colículo inferior de ratos

Investigamos o envolvimento dos aminoácidos excitatórios na expressão das reações defensivas processadas no colículo inferior. Para tanto, fizemos microinjeções de doses crescentes do aminoácido excitatório nmda no colículo inferior de ratos colocados no interior de uma arena circular e esta droga induziu reações graduais aversivas. Adicionalmente, verificamos a influência do nmda sobre as respostas autonômicas e verificamos alterações nos registros de pressão arterial e frequência cardíaca. Assim, e sugerido que esta substância esteja exercendo um papel crítico no processamento de estados aversivos no colículo inferior (AU)

Estudo dos efeitos da morfina sobre os substratos neurais da aversão no colículo inferior de ratos

Investigamos a mediação química das respostas aversivas processadas a nível colículo inferior (ci) através de microinjeção de morfina. Verificamos que baixas doses atenuam efeitos aversivos induzidos por estimulação elétrica e este efeito e bloqueado por material indicando que esta ação e mediada por receptores opióides. Paradoxalmente altas dose promovem reações aversivas indicando uma interação entre mecanismos opióides nesta estrutura (AU)