Flavonostilbenes natural hybrids from Rhamnoneuron balansae as potential antitumors targeting ALDH1A1: molecular docking, ADMET, MM-GBSA calculations and molecular dynamics studies.

Several studies have linked Cancer stem cells (CSCs) to cancer resistance development to chemotherapy and radiotherapy. ALDH1A1 is a key enzyme that regulates the gene expression of CSCs and creates an immunosuppressive tumor microenvironment. It was reported that quercetin and resveratrol were among the inhibitors of ALDH1A1. In early 2022, it was reported that new 11 flavonostilbenes (rhamnoneuronal D-N) were isolated from Rhamnoneuron balansae as potential antiaging natural products. Rhamnoneuronal H (5) could be envisioned as a natural hybrid of quercetin and resveratrol. It was therefore hypothesized that 5 and its analogous isolates rhamnoneuronal D-G (1-4) and rhamnoneuronal I-N (6-11) would have potential ALDH1A1 inhibitory activity. To this end, all isolates were subjected to molecular docking, MM-GBSA, ADMET, and molecular dynamics simulations studies to assess their potential as new leads for cancer treatment targeting ALDH1A1. In silico findings revealed that natural hybrid 5 has a similar binding affinity, judged by MM-GBSA, to the ALDH1A1 active site when compared to the co-crystalized ligand (-64.71 kcal/mole and -64.12 kcal/mole, respectively). Despite having lesser affinity than that of the co-crystalized ligand, the rest of the flavonostilbenes, except 2-4, displayed better binding affinities (-37.55 kcal/mole to -58.6 kcal/mole) in comparison to either resveratrol (-34.44 kcal/mole) or quercetin (-36.48 kcal/mole). Molecular dynamic simulations showed that the natural hybrids 1, 5-11 are of satisfactory stability up to 100 ns. ADMET outcomes indicate that these hybrids displayed acceptable properties and hence could represent an ideal starting point for the development of potent ALDH1A1 inhibitors for cancer treatment.Communicated by Ramaswamy H. Sarma.

Formulation and Optimization of Alogliptin-Loaded Polymeric Nanoparticles: In Vitro to In Vivo Assessment.

The nano-drug delivery system has gained greater acceptability for poorly soluble drugs. Alogliptin (ALG) is a FDA-approved oral anti-hyperglycemic drug that inhibits dipeptidyl peptidase-4. The present study is designed to prepare polymeric ALG nanoparticles (NPs) for the management of diabetes. ALG-NPs were prepared using the nanoprecipitation method and further optimized by Box−Behnken experimental design (BBD). The formulation was optimized by varying the independent variables Eudragit RSPO (A), Tween 20 (B), and sonication time (C), and the effects on the hydrodynamic diameter (Y1) and entrapment efficiency (Y2) were evaluated. The optimized ALG-NPs were further evaluated for in vitro release, intestinal permeation, and pharmacokinetic and anti-diabetic activity. The prepared ALG-NPs show a hydrodynamic diameter of between 272.34 nm and 482.87 nm, and an entrapment efficiency of between 64.43 and 95.21%. The in vitro release data of ALG-NPs reveals a prolonged release pattern (84.52 ± 4.1%) in 24 h. The permeation study results show a 2.35-fold higher permeation flux than pure ALG. ALG-NPs exhibit a significantly (p < 0.05) higher pharmacokinetic profile than pure ALG. They also significantly (p < 0.05) reduce the blood sugar levels as compared to pure ALG. The findings of the study support the application of ALG-entrapped Eudragit RSPO nanoparticles as an alternative carrier for the improvement of therapeutic activity.

Isatin derivatives as broad-spectrum antiviral agents: the current landscape.

In recent decades, several viruses have resulted in large outbreaks with serious health, economic and social consequences. The current unprecedented outbreak of the new coronavirus, SARS-COV-2, necessitates intensive efforts for delivering effective therapies to eradicate such a deadly virus. Isatin is an opulent heterocycle that has been proven to provide tremendous opportunities in the area of drug discovery. Over the last fifty years, suitably functionalized isatin has shown remarkable and broad-spectrum antiviral properties. The review herein is an attempt to compile all of the reported information about the antiviral activity of isatin derivatives with an emphasis on their structure-activity relationships (SARs) along with mechanistic and molecular modeling studies. In this regard, we are confident that the review will afford the scientific community a valuable platform to generate more potent and cost-effective antiviral therapies based on isatin templates.

Xanthone: A Promising Antimycobacterial Scaffold.

BACKGROUND: Tuberculosis (TB) is one of the infectious diseases associated with high rate of morbidity and mortality and still remains one of the top-ten leading causes of human death in the world. The development of new anti-TB drugs is mandatory due to the existence of latent infection as well as the expansion of the resistant Mycobacterium tuberculosis (MBT) strains. Xanthones encompass a wide range of structurally diverse bioactive compounds, obtained either naturally or through chemical synthesis. There is a growing body of literature that recognizes the antitubercular activity of xanthone derivatives. OBJECTIVE: The objective of this review is to highlight the main natural sources along with the critical design elements, structure-activity relationships (SARs), modes of action and pharmacokinetic profiles of xanthone-based anti-TB compounds. METHODS: In the present review, the anti-TB activity of xanthones reported in the literature from 1972 to date is presented and discussed. RESULTS: Exploration of xanthone scaffold led to the identification of several members of this class having superior activity against both sensitive and resistant MBT strains with distinctive mycobacterial membrane disrupting properties. However, studies regarding their modes of action, pharmacokinetic properties and safety are limited. CONCLUSION: Comprehendible data and information are afforded by this review and it would certainly provide scientists with new thoughts and means which will be conducive to design and develop new drugs with excellent anti-TB activity through exploration of xanthone scaffold.