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Alzheimer's disease (AD) is a prevalent neurological illness that affects over 80% of aged adults globally in cases of dementia. Although the exact pathophysiological causes of AD remain unclear, its pathogenesis is primarily driven by several distinct biochemical alterations: (i) the accumulation of toxic Aβ plaques, (ii) the hyperphosphorylation of tau proteins, (iii) oxidative stress resulting in cell death, and (iv) an imbalance between the two main neurotransmitters, glutamate and acetylcholine (ACh). Currently, there are very few medications available and no treatment. Presently marketed medications include memantine, an N-methyl-d-aspartate receptor (NMDA) antagonist, and acetylcholinesterase (AChE) inhibitors: rivastigmine, donepezil, and galantamine. Unfortunately, these medications are only useful in the initial stages of AD. The mentioned medications only provide symptomatic relief and do not slow down the disease progression in the advanced stages. Therefore, there is an urgent need to develop potential candidates to treat AD, symptomatically and therapeutically. Many research groups focus on natural products due to their diverse therapeutic profiles and easy availability. One such natural product is deoxyvasicinone, isolated from Adhatoda vasica. Given its broad pharmacological profile, various researchers have developed semisynthetic hybrids of deoxyvasicinone to address multifaceted diseases like AD. In this review article, we tried to summarize the semisynthetic hybrids of deoxyvasicinone developed over the past decade (2014-2024) for managing AD. We focus on their design, pharmacological activity, and structure-activity relationship (SAR) analysis. We hope this review enhances the reader's understanding of future exploratory options for deoxyvasicinone hybrids in AD management.

Glycyrrhetinic acid (GA) is a naturally occurring triterpene compound. The aim of this study was to employ the pharmacophore hybrid strategy to merge GA with various dithiocarbamates and obtain novel compounds with better antitumor activities. We present a two-step synthetic protocol wherein the GA derivative underwent reaction with carbon disulfide and various secondary amines in a one-pot manner under mild conditions, facilitating the preparation of a series of structurally novel GA-dithiocarbamate derivatives. Bioassay screening revealed that the representative compound 3c demonstrated the capacity to reduce the mitochondrial membrane potential in Hep3B and Huh-7 cells, induce nuclear apoptosis, inhibit invasion and migration, and prompt both early and late apoptosis. Furthermore, our research findings indicated that this apoptotic phenomenon may be associated with the expression of Bcl-2, Bax, Bak, PARP, and cleaved-PARP proteins. Utilizing network pharmacology for predicting core targets and signaling pathways of compound 3c for hepatocellular carcinoma (HCC) treatment involved employing molecular docking models to demonstrate high affinity between compound and target protein. In conjunction with Western blot analysis, compound 3c may impact HCC through the PI3K-AKT-mTOR pathway.

5-(3',4'-Dihydroxyphenyl)-γ-valerolactone (VL) is a bioactive metabolite resulting from the gut microbial metabolism of proanthocyanidins and flavonoids, known for its health-promoting effects, including antidiabetic and anti-inflammatory activities. Although VL has been observed in different in vivo studies, its pre-absorption, distribution, metabolism, excretion, toxicity (ADMET) properties have rarely been investigated. This study aims to address this gap by evaluating the pre-ADMET properties of VL for the first time. Also, the understanding of these properties is significant for correlating the encountered activities to this metabolite. In vitro absorption studies revealed that VL is rapidly metabolized and absorbed as its sulfate phase II conjugate (valerolactone sulfate), which enters systemic circulation and mildly activates the Breast Cancer Resistance Protein efflux transporter. In human S9 liver fraction, a mixture of liver enzymes used to simulate in vivo liver metabolism, VL is metabolized into glucuronic phase II conjugates (valerolactone glucuronide 1 [VLG1] and 2 [VLG2]) with a half-life of 8.72 min and an 80% conversion rate. In human liver microsomes, VL is metabolized at a slower rate (half-life of 23.08 min), suggesting that oxidative metabolism is secondary. Additionally, VL did not activate the pregnane X receptor or inhibit Cytochrome P3A4 (CYP3A4) and Cytochrome P1A2 (CYP1A2) enzymes, indicating no risk of herb-drug interactions with coadministered prescription drugs.

Multidrug resistance (MDR) due to the overexpression of the P-glycoprotein (P-gp) efflux pump remains a significant challenge in cancer therapy, also in breast cancer. Traditional pharmacological approaches have focused on using inhibitors to modulate P-gp expression and function. Curcumin, a polyphenol derived from Curcuma longa L., is one of the most extensively studied natural compounds with the potential as an effective P-gp inhibitor. Despite its promising attributes, the clinical application of P-gp inhibitors is complicated by P-gp's presence in healthy cells, such as those in the intestinal barrier and blood-brain barrier, which can lead to increased toxicity. To address these challenges, we developed a novel multifunctional nanomaterial by covalently bonding halloysite nanotubes (HNTs) with hectorite (Ht) and loading it with curcumin and doxorubicin. The efficacy of the co-delivery of curcumin and doxorubicin by HNTs-Ht nanomaterial was evaluated by cytotoxicity assays on MCF-7R cells, both in two-dimensional (2D) and in three-dimensional (3D) models. The obtained data show that curcumin causes increased doxorubicin accumulation by acting as a substrate for P-gp transport and as a stimulator of the adenosine triphosphate (ATP)-dependent drug efflux transporter on a doxorubicin-resistant breast cancer cell line. The results suggest that the HNTs-Ht nanomaterial could provide a promising approach to improve chemotherapy effectiveness by overcoming MDR and enhancing treatment outcomes.

Colorectal cancer (CRC) continues to be a significant health challenge, necessitating the development of efficient therapeutic strategies. Drug repurposing, which involves the use of existing medications for new purposes, presents a promising opportunity. Metformin, a widely used antidiabetic drug, has demonstrated potential anticancer effects. To enhance its efficacy, we formulated nano-metformin, metformin encapsulated within pectin nanoparticles. Our study aimed to evaluate the superiority of nano-metformin over free metformin in treating CRC. The cytotoxicity of both metformin and nano-metformin on Caco-2 CRC cells was assessed using the MTT assay, revealing a significant dose-dependent inhibition of cell growth using nano-metformin. The anti-inflammatory potential was evaluated by measuring the levels of nitric oxide and the pro-inflammatory cytokines IL-2 and IL-6 following lipopolysaccharide (LPS) induction, and the results revealed that treating LPS-induced cells with nano-metformin significantly reduced the production of these inflammatory mediators. To elucidate the mechanism of cell death, we employed an acridine orange/ethidium bromide staining assay, which revealed the enhancement of apoptotic cell death following treatment with nano-metformin. Additionally, we examined the expression of key apoptotic regulators using real-time qPCR. Nano-metformin, in particular, significantly downregulated the expression of the antiapoptotic markers Bcl-2 and Survivin while upregulating the proapoptotic caspases 3, 7, and 9. The comet assay revealed significant DNA damage induced by treatment with the nano-metformin compared with that in the free form. Moreover, nano-metformin significantly reduced the migration ability of cells. In conclusion, our work revealed the superior efficacy of our formulated nanoform over free metformin, highlighting its potential as a promising therapeutic agent for CRC treatment.

Within the last two decades, the European Medicines Agency and the US Food and Drug Administration have approved several gene therapies. One category is oligonucleotide therapeutics, which allow for the regulation of the expression of target genes. Besides already approved therapeutics, there are several preclinical and clinical trials ongoing. The World Anti-Doping Agency prohibits the use of "nucleic acids or nucleic acid analogs that may alter genome sequences and/or alter gene expression by any mechanism" as a nonspecified method at all times. Hence, the administration of nucleic acids or analogs by athletes would cause an Anti-Doping Rule Violation. Herein, we discuss types of oligonucleotide therapeutics, their potential to be misused in sports, and considerations to sample preparation and mass spectrometric approaches with regard to antidoping analysis.

Lactones, a diverse and abundant class of molecules found in nature, exhibit a wide range of bioactivities, including anti-inflammatory, anticancer, and antibacterial effects. Among them, acyl homoserine lactones (AHSLs) play a crucial role in quorum sensing, influencing bacterial pathogenicity and biofilm formation in Gram-negative bacteria. Paraoxonases (PONs), calcium-containing enzymes known for their lactonase activity, have been shown to hydrolyze AHSLs and reduce the biofilm formation of several pathogenic bacteria. In this study, we explored the potential lactonase activity of a class of zinc(II) enzymes, the carbonic anhydrases (CAs), aiming to uncover new insights into their catalytic versatility. Using LC-MS and MS/MS analyses, we investigated the lactonase activity of CAs and assessed several lactones through a stopped-flow kinetic assay as substrates/inhibitors. Our findings reveal that lactones are novel "prodrug" inhibitors of CAs, with lactones DHC and 6 showing the most promising inhibition constants (K_Is) in the low micromolar range against both human and bacterial isozymes.

Tyrosyl DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which are enzymes involved in the repair of DNA, are regarded as promising targets for the development of new anticancer drugs. In this study, a series of imidazolidine-2,4-diones, 2,4,5-triones, and 2-thioxoimidazolidine-4,5-diones based on dehydroabietylamine (DHAAm) were synthesized. The inhibitory activity of the new compounds against TDP1 and TDP2, as well as their cytotoxic characteristics, were evaluated. All types of heterocyclic DHAAm derivatives demonstrated effective inhibition of TDP1 in the micromolar range, with IC₅₀ values in the range of 0.63-4.95 µM. It was observed that only the 2-thioxoimidazolidine-4,5-diones were TDP2 inhibitors, representing the first class of dual TDP1/TDP2 inhibitors among DHAAm derivatives. The findings of this study may contribute to an enhanced comprehension of the subsequent design of novel dual TDP1/TDP2 inhibitors for the further development of new antitumor agents.

Diseases caused by protozoan parasites represent a huge challenge to global health care, due to the lack of selective and efficient treatments for the management and spreading of such complex pathologies. The protozoans Trypanosoma cruzi (T. cruzi) and Leishmania spp. are the etiological agents of the so-called neglected tropical diseases (NTDs), that is, Chagas disease (CD) and leishmaniasis, respectively. In such a context, the metalloenzymes carbonic anhydrases (CAs; EC 4.2.1.1) emerged as potential protozoan druggable enzymes, being involved in the parasites' life cycle. Several studies suggested the relevance of the protozoan-expressed CAs as future candidates for the management of NTDs.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) papain-like cysteine protease (PLpro) represents one of only two essential cysteine proteases involved in the regulation of viral replication. It, therefore, qualifies as a promising therapeutic target for the development of antiviral agents. We identified a previously synthesized protease inhibitor, resulting from an earlier project, as a PLpro inhibitor and crafted a structure-activity relationship around the hit, leading to the more potent inhibitors ZHAWOC6941 (17h) and ZHAWOC25153 (17o) displaying IC₅₀ values of 8 and 7 µM, respectively. The two compounds represent a new class of PLpro inhibitors and, with single-digit micromolar IC₅₀ values, are comparable to inhibitors found in the literature.