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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.

As the world transitions from the acute phase of the COVID-19 pandemic caused by SARS-CoV-2, the scientific community continues to explore various therapeutic avenues to control its spread and mitigate its ongoing effects. Among the promising candidates are heparan sulfate (HS) and enoxaparin (EX), which have emerged as potential virus inhibitors. HS, a type of glycosaminoglycan, plays a prominent role in the attachment of the virus to host cells. At the same time, EX, a low-molecular-weight heparin, is being investigated for its ability to disrupt the interaction between the spike protein of SARS-CoV-2 and the ACE2 receptor in human cells. Understanding the mechanisms through which these substances operate could lay the foundation for new strategies in the ongoing management of COVID-19. This study aimed to examine the details of SARS-CoV-2's entry mechanisms and the role of HS in this process. Furthermore, it examines EX's mechanism of action, highlighting how it potentially inhibits SARS-CoV-2. The interactions between HS and the virus, alongside in-vitro and in-silico inhibition studies with HS and EX, are critically analyzed to assess their antiviral efficacy. Additionally, the antiviral activity of sulfated polysaccharides and the potential therapeutic applications of these findings are discussed.

Alzheimer's disease (AD) is a neurodegenerative disorder and a principal basis of dementia in the elderly population globally. Recently, human carbonic anhydrases (hCAs, EC 4.2.1.1) were demonstrated as possible new targets for treating AD. hCAs are vital for maintaining pH balance and performing other physiological processes as they catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. Current research indicates that hCA plays a role in brain functions critical for transmitting neural signals. Activation of carbonic anhydrase (CA) has emerged as a promising avenue in addressing memory loss and cognitive issues. Conversely, the exploration of CA inhibition represents a novel frontier in this field. By enhancing glial fitness and cerebrovascular health and blocking amyloid-β (Aβ)-induced mitochondrial dysfunction pathways, cytochrome C (CytC) release, caspase 9 activation, and H₂O₂ generation in neurons, CA inhibitors improve cognition and lessen the pathology caused by Aβ. Recent research has pushed hCAs into the spotlight as critical players in AD pathogenesis and precise therapeutic targets. The captivating dilemma of choosing between hCA inhibitors and activators looms large, as inhibitors reduce Aβ aggregation and improve cerebral blood flow, while activators enhance cerebrovascular functions and restore pH balance. The current review sheds light on the clinical evidence for hCAs and the roles of inhibitors and activators in AD. Additionally, this review offers a fascinating outlook on the data that may aid medicinal chemists in designing and developing new leads that are more effective and selective for upcoming in vitro and in vivo studies, allowing for the discovery and introduction of novel drug candidates for the treatment of AD to the market and into the clinical pipeline.

DZH2, a dual inhibitor of the chemokine receptors CCR5 and CXCR4, was discovered from virtual screening for CCR5 antagonists. In specific Ca²⁺ chemokine signaling assays, DZH2 displayed low micromolar IC₅₀ values at both chemokine receptors. Its binding to intracellular allosteric binding sites of CCR5 and CXCR4 was confirmed by MD simulations and binding free-energy calculations. DZH2 is superior to the CCR5 antagonist maraviroc in terms of its inhibitory activity on the growth of two breast cancer cell lines. In MCF7 and MDA-MB-231 cells, DZH2 was a >100-fold more potent inhibitor of cell viability compared to maraviroc. DZH2 (6.7 µM) reduced migration of MDA-MB-231 cells to 4% compared to 50% inhibition of migration caused by maraviroc (780 µM). Also, DZH2 was a significantly more potent inhibitor of colony formation in MDA-MB-231 cells than maraviroc. In MCF10 cells, DZH2 caused no alteration in the gene expression with respect to cellular pathways mediating cell death, indicating its selectivity to breast cancer cells.

A series of multi-functional tyrosinase inhibitors derived from kojic acid (KA) and hydroquinone-like diphenols were designed and synthesized using click chemistry. The in vitro enzymatic assay revealed that all compounds containing a free enolic structure showed excellent activity against tyrosinase (IC₅₀ = 0.14-3.7 µM), being significantly more potent than KA. The most active compounds were catechol (6c) and α-naphthol (6i) analogs with 138- and 96-fold higher potency than KA. On the other hand, all free phenolic compounds (6a-c and 6g-j) derived from aromatic diols showed outstanding free radical scavenging activities superior to KA. Certainly, the α-naphthol derivative 6i with IC₅₀ = 10.1 µM was the most active anti-oxidant, being as potent as quercetin. The SAR analysis indicated that the enolic head of the conjugate molecules mainly contributes to the anti-tyrosinase activity, and the free phenolic part of the molecules can offer anti-oxidant potency. The anti-melanogenic assay of the most promising derivative, 6i, against melanoma (B16F10) cells demonstrated that the prototype compound 6i can significantly reduce the melanin content, more effectively than KA. By using a conjugation strategy, we have improved the tyrosinase inhibitory and radical scavenging activity in the multi-functional agents such as 6i over the parent compound KA, being potentially useful in the treatment of hyperpigmentation and other skin disorders.

Rheumatoid arthritis (RA) is a persistent autoimmune disorder predominantly affecting the joint structures, eliciting inflammatory responses, and ultimately leading to degenerative changes without proper medical intervention. Ultimately, this can severely impair joint function and impact the patient's quality of life. Current treatment approaches include disease-modifying anti-rheumatic drugs, non-steroidal anti-inflammatory drug, corticosteroids, and biologic therapies for RA management. The current study contributes to the ongoing advancements in RA treatment. d-Limonene is a monocyclic monoterpene. It is present in essential oils of various aromatic plants, such as Lippia alba and Artemisia dracunculus, and in citrus fruits such as lemon and orange. It has reported anti-inflammatory and anti-nociceptive properties and was selected for the current study as a potential anti-arthritic candidate. It was administered at three dosages (25, 50, 100 mg/kg, b.w., p.o) in Complete Freund's adjuvant-induced arthritic rats over 28 days. The efficacy of the compound was compared to piroxicam, a widely used standard drug for treating RA. The anti-arthritic activity of the compound was assessed by measuring arthritic scoring and plethysmometry at both baseline and post-intervention stages. Additional confirmation of the investigation was sought by performing biochemical and hematological activities. Moreover, quantitative polymerase chain reaction was employed to determine the levels of messenger RNA expression for transcription factors such as tumor necrosis factor-α, interleukin (IL)-1β, nuclear factor-κB, matrix metalloproteinase-3, IL-6, and IL-4 in the blood. The levels of PGE2 were evaluated by enzyme-linked immunosorbent assay. The histopathological and radiographic studies were also carried out for further confirmation. The results of these findings supported our assertion regarding the anti-arthritic potential of the compound.

Pazopanib hydrochloride (PZH) is a Biopharmaceutics Classification System class II drug that faces challenges at the formulation forefront including low aqueous solubility (0.043 mg/mL) and poor oral bioavailability (14-39%). The present investigation aimed to develop a self-microemulsifying drug delivery system (SMEDDS) of PZH using a blend of Capryol® 90, Labrasol®, and propylene glycol to improve its solubility. Furthermore, a sustained-release SMEDDS-based gastroretentive floating system was developed and optimized using the Central Composite Design approach of DoE. The optimized SMEDDS-based in situ gelling raft, R-SM-PZH, exhibited minimal floating lag time (3.09 ± 0.8 s), optimal viscosity (1229.4 ± 20.9 cP) and density (0.327 ± 0.15 g/mL) as compared to other formulations under study. Additionally, R-SM-PZH was evaluated for its in vitro dissolution in FaSSGF and FeSSGF, pharmacokinetic profile, and MTT assay (against NCI-H460 lung cancer cells) compared to pure PZH. A 12 h sustained release, three-fold augmentation in dissolution rate and bioavailability, and 15-fold enhancement in cytotoxicity were observed in comparison to pure PZH. Thus, the SMEDDS-based in situ gelling raft presents a promising approach to advancing the developability potential of PZH.

Psoriasis is a chronic inflammatory skin disease that affects patients' quality of life. This study aimed to enhance the efficacy of topical application of fluticasone propionate (FP) using a eucalyptus oil-based nanoemulsion, an oil possessing anti-inflammatory activity and extracted from the leaves, fruits, and buds of Eucalyptus globulus or Eucalyptus maidenii, to improve the skin deposition of FP and aid its anti-inflammatory effect. Box-Behnken design was employed to optimize NE formulations, which were characterized for globule size, zeta potential, polydispersity index, rheological behavior, microscopic morphology, ex vivo skin permeation/deposition, and in vivo efficacy using imiquimod-induced psoriatic lesions. The optimized formulation depicted a droplet size of 188 ± 22.4 nm, a zeta potential of -17.63 ± 1.66 mV, and a viscosity of 204.9 mPa s. In addition to the increased FP retention in different skin layers caused by the NE and the reduced PASI score compared to the marketed cream, the levels of inflammatory cytokines IL-1α, IL-6, IL17a were markedly lowered, indicating the improved anti-psoriatic curable efficacy of the optimized formulation in comparison to the FP-marketed product.

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.