Synthetic Derivatives against Wild-Type and Non-Wild-Type Sporothrix brasiliensis: In Vitro and In Silico Analyses

Recently, the well-known geographically wide distribution of sporotrichosis in Brazil, combined with the difficulties of effective domestic feline treatment, has emphasized the pressing need for new therapeutic alternatives. This work considers a range of synthetic derivatives as potential antifungals against Sporothrix brasiliensis isolated from cats from the hyperendemic Brazilian region. Six S. brasiliensis isolates from the sporotrichotic lesions of itraconazole responsive or non-responsive domestic cats were studied. The minimum inhibitory concentrations (MICs) of three novel hydrazone derivatives and eleven novel quinone derivatives were determined using the broth microdilution method (M38-A2). In silico tests were also used to predict the pharmacological profile and toxicity parameters of these synthetic derivatives. MICs and MFCs ranged from 1 to >128 µg/mL. The ADMET computational analysis failed to detect toxicity while a good pharmacological predictive profile, with parameters similar to itraconazole, was obtained. Three hydrazone derivatives were particularly promising candidates as antifungal agents against itraconazole-resistant S. brasiliensis from the Brazilian hyperendemic region. Since sporotrichosis is a neglected zoonosis currently spreading in Latin America, particularly in Brazil, the present data can contribute to its future control by alternative antifungal drug design against S. brasiliensis, the most virulent and prevalent species of the hyperendemic context.

Biomedical Applications and Bioavailability of Curcumin—An Updated Overview

Curcumin, a yellow-colored molecule derived from the rhizome of Curcuma longa, has been identified as the bioactive compound responsible for numerous pharmacological activities of turmeric, including anticancer, antimicrobial, anti-inflammatory, antioxidant, antidiabetic, etc. Nevertheless, the clinical application of curcumin is inadequate due to its low solubility, poor absorption, rapid metabolism and elimination. Advancements in recent research have shown several components and techniques to increase the bioavailability of curcumin. Combining with adjuvants, encapsulating in carriers and formulating in nanoforms, in combination with other bioactive agents, synthetic derivatives and structural analogs of curcumin, have shown increased efficiency and bioavailability, thereby augmenting the range of applications of curcumin. The scope for incorporating biotechnology and nanotechnology in amending the current drawbacks would help in expanding the biomedical applications and clinical efficacy of curcumin. Therefore, in this review, we provide a comprehensive overview of the plethora of therapeutic potentials of curcumin, their drawbacks in efficient clinical applications and the recent advancements in improving curcumin’s bioavailability for effective use in various biomedical applications.

Discovering and harnessing oxidative enzymes for chemoenzymatic synthesis and diversification of anticancer camptothecin analogues

Semi-synthetic derivatives of camptothecin, a quinoline alkaloid found in the Camptotheca acuminata tree, are potent anticancer agents. Here we discovered two C. acuminata cytochrome P450 monooxygenases that catalyze regio-specific 10- and 11-oxidations of camptothecin, and demonstrated combinatorial chemoenzymatic C-H functionalizations of the camptothecin scaffold using the new enzymes to produce a suite of anticancer drugs, including topotecan (Hycamtin®) and irinotecan (Camptosar®). This work sheds new light into camptothecin metabolism, and represents greener approaches for accessing clinically relevant camptothecin derivatives.

Linarin, a Glycosylated Flavonoid, with Potential Therapeutic Attributes: A Comprehensive Review

Many flavonoids, as eminent phenolic compounds, have been commercialized and consumed as dietary supplements due to their incredible human health benefits. In the present study, a bioactive flavone glycoside linarin (LN) was designated to comprehensively overview its phytochemical and biological properties. LN has been characterized abundantly in the Cirsium, Micromeria, and Buddleja species belonging to Asteraceae, Lamiaceae, and Scrophulariaceae families, respectively. Biological assessments exhibited promising activities of LN, particularly, the remedial effects on central nervous system (CNS) disorders, whereas the remarkable sleep enhancing and sedative effects as well as AChE (acetylcholinesterase) inhibitory activity were highlighted. Of note, LN has indicated promising anti osteoblast proliferation and differentiation, thus a bone formation effect. Further biological and pharmacological assessments of LN and its optimized semi-synthetic derivatives, specifically its therapeutic characteristics on osteoarthritis and osteoporosis, might lead to uncovering potential drug candidates.

Advances in Phenazines over the Past Decade: Review of Their Pharmacological Activities, Mechanisms of Action, Biosynthetic Pathways and Synthetic Strategies

Phenazines are a large group of nitrogen-containing heterocycles, providing diverse chemical structures and various biological activities. Natural phenazines are mainly isolated from marine and terrestrial microorganisms. So far, more than 100 different natural compounds and over 6000 synthetic derivatives have been found and investigated. Many phenazines show great pharmacological activity in various fields, such as antimicrobial, antiparasitic, neuroprotective, insecticidal, anti-inflammatory and anticancer activity. Researchers continued to investigate these compounds and hope to develop them as medicines. Cimmino et al. published a significant review about anticancer activity of phenazines, containing articles from 2000 to 2011. Here, we mainly summarize articles from 2012 to 2021. According to sources of compounds, phenazines were categorized into natural phenazines and synthetic phenazine derivatives in this review. Their pharmacological activities, mechanisms of action, biosynthetic pathways and synthetic strategies were summarized. These may provide guidance for the investigation on phenazines in the future.

Antimicrobial Activity Derivatives 2H-pirano[2,3-c]piridines against Pathogens of Intestinal Yersiniosis

Background: An important aspect in the treatment of patients with intestinal yersiniosis is the administration of effective antibiotic therapy. Performed research aimed to determine the spectrum and level of antimicrobial activity of 2H-pyrano[2,3- c]pyridine derivatives on the museum and clinical strains of gram-negative microorganisms Yersinia enterocolitica. Methodology: The object of the study was 28 synthetic derivatives of 2H-pyrano[2,3- c]pyridine. The compounds were studied according to their chemical structure. We used the method of serial dilutions in Muller-Hinton liquid nutrient medium with a museum’s and clinical strains of Y.enterocolitica. Results: Studies indicate the promise of further study of the properties of 2H- pyrono[2,3-c]pyridine to create an effective antimicrobial medicine. According to the results of studies on action of antimicrobial compounds synthesized on the basis of 2H-pyrano[2,3-с]pyridine derivatives, it was found that the MIC of compounds for all Y. enterocolitica strains was 100.0 μg/ml. The MBCC of most cultures of Yersinia (72.3 %) was 200.0 μg/ml. Compound 2{3} had a pronounced antiyersiniotic activity, the inhibitory effect of which was manifested at a concentration of 25.0 μg/ml. Retarding the growth of most Yersinia strains (95.3%) with a MIC of 50.0 μg/ml, the MIC of compounds ranged from 50.0 to 200.0 μg/ml. After statistical data processing, pyridine derivatives (compounds 2{3} and 3{5}) were identified, possessing an effective bacteriostatic and bactericidal effect on Y. enterocolitica strains. Conclusions: The results of the research showed a high antimicrobial activity of 2H- pyrano[2,3-c]pyridine derivatives. The highest activity against Y. enterocolitica was found for 2-N2-arylimino-5-hydroxy-methyl-8-methyl-2H-pyrano[2,3-c]pyridine-3-N1- aricarboxamide derivatives.

The Antiviral Effect of Novel Steroidal Derivatives on Flaviviruses

Flaviviruses are the major emerging arthropod-borne pathogens globally. However, there is still no practical anti-flavivirus approach. Therefore, existing and emerging flaviviruses desperately need active broad-spectrum drugs. In the present study, the antiviral effect of steroidal dehydroepiandrosterone (DHEA) and 23 synthetic derivatives against flaviviruses such as Japanese encephalitis virus (JEV), Zika virus (ZIKV), and Dengue virus (DENV) were appraised by examining the characteristics of virus infection both in vitro and in vivo. Our results revealed that AV1003, AV1004 and AV1017 were the most potent inhibitors of flavivirus propagation in cells. They mainly suppress the viral infection in the post-invasion stage in a dose-dependent manner. Furthermore, orally administered compound AV1004 protected mice from lethal JEV infection by increasing the survival rate and reducing the viral load in the brain of infected mice. These results indicate that the compound AV1004 might be a potential therapeutic drug against JEV infection. These DHEA derivatives may provide lead scaffolds for further design and synthesis of potential anti-flavivirus potential drugs.

Ginger metabolites and metabolite-inspired synthetic products modulate intracellular calcium and relax airway smooth muscle

Asthma affects millions of people worldwide and its prevalence is increasing. It is characterized by chronic airway inflammation, airway remodeling, and pathologic bronchoconstriction, and it poses a continuous treatment challenge with very few new therapeutics available. Thus, many asthmatics turn to plant-based complementary products, including ginger, for better symptom control, indicating an unmet needed for novel therapies. Previously, we demonstrated that 6-shogaol (6S), the primary bioactive component of ginger, relaxes human airway smooth muscle (hASM) likely by inhibition of phosphodiesterases (PDEs) in the b-adrenergic (cyclic nucleotide PDEs) and muscarinic (phospholipase C, PLC) receptor pathways. However, oral 6S is extensively metabolized and it is unknown if the resulting metabolites remain bioactive. Here we screened all the known human metabolites of 6S and several metabolite-based synthetic derivatives to better understand their mechanism of action and structure-function relationships. We demonstrate that several metabolites and metabolite-based synthetic derivatives are able to prevent Gq-coupled stimulation of intracellular calcium [Ca2+]i and inositol triphosphate (IP3) synthesis by inhibiting PLC, similar to the parent compound 6S. We also show that these compounds prevent re-contraction of ASM after b-agonist relaxation likely by inhibiting PDEs. Furthermore, they potentiate isoproterenol-induced relaxation. Importantly, moving beyond cell-based assays, metabolites also retain the functional ability to relax Gq-coupled-contractions in upper (human) and lower (murine) airways. The current study indicates that, although oral ginger may be metabolized rapidly, it retains physiologic activity through its metabolites. Moreover, we are able to use naturally occurring metabolites as inspiration to develop novel therapeutics for brochoconstrictive diseases.

Computational modeling and experimental validation of the EPI-X4/CXCR4 complex allows rational design of small peptide antagonists

EPI-X4, a 16-mer fragment of albumin, is a specific endogenous antagonist and inverse agonist of the CXC-motif-chemokine receptor 4 (CXCR4) and thus a key regulator of CXCR4 function. Accordingly, activity-optimized synthetic derivatives of EPI-X4 are promising leads for the therapy of CXCR4-linked disorders such as cancer or inflammatory diseases. We investigated the binding of EPI-X4 to CXCR4, which so far remained unclear, by means of biomolecular simulations combined with experimental mutagenesis and activity studies. We found that EPI-X4 interacts through its N-terminal residues with CXCR4 and identified its key interaction motifs, explaining receptor antagonization. Using this model, we developed shortened EPI-X4 derivatives (7-mers) with optimized receptor antagonizing properties as new leads for the development of CXCR4 inhibitors. Our work reveals the molecular details and mechanism by which the first endogenous peptide antagonist of CXCR4 interacts with its receptor and provides a foundation for the rational design of improved EPI-X4 derivatives.

Evaluation of the in vitro trypanocidal activity of triterpenes uvaol, betulinic acid and its semi-synthetic derivatives against the Y strain of Trypanosoma cruzi / Avaliação da atividade tripanocida in vitro dos triterpenos uvaol, ácido betulínico e seus derivados semissintéticos contra a cepa Y de Trypanosoma cruzi

Chagas disease is a neglected tropical disease that affects millions of people worldwide. Trypanosoma cruzi (T. cruzi) is the causative agent of Chagas disease and its transmission occurs through blood meal by triatomine bugs, being oral transmission the most common form. More than 100 years after the disease´s discovery, benzonidazole is the only efficient drug against T. cruzi; however, this drug has numerous serious side effects and is only efficient in the acute phase of the disease. Natural products, such as triterpenes, have been an important source of new substances to combat human parasitology. In this study, two triterpenes, uvaol and betulinic acid, were tested against the parasite T. cruzi. The best results of in vitro tests were observed for uvaol with an IC50 value of 70.3 µM against the trypomastigost forms and an IC50 value of 90.6 µM against the amastigost forms. Three semi-synthetic derivatives of betulinic acid were obtained; the acetylated derivative showed excellent results against trypomastigotes forms (IC50 = 15.67 µM), but was not active against the amastigotes forms. The cytotoxic MTT test was also performed on LLCMK2 cells (Macaca mullata kidney epithelial cells) and betulinic acid showed the highest selectivity index (SI) with a value of 1.3.