Evolution and challenges of opioids in pain management: Understanding mechanisms and exploring strategies for safer analgesics
This article explores the mechanisms of opioid activity in cells, emphasizing the role of biased agonism in the analgesic and adverse effects of opioids. We further reviewed strategies to mitigate the side effects, including the development of biased agonists targeting G-proteins, exploration of opioid receptor heterodimers, allosteric activation, and selective targeting of receptor splice variants. Insights into the sodium channel ’s role and bitopic modulators also offer new avenues for drug design. The quest to develop safer and more effective analgesics while minimizing adverse effects drives ongoing research. The co...
Source: Medicinal Chemistry Research - February 29, 2024 Category: Chemistry Source Type: research
Adenine derivatives as inhibitors of the casein kinase CK1delta enzyme
AbstractOverexpression of CK1 δ has been associated to the development of cancer and neurodegenerative disorders, making ligands of this protein very promising drug candidates for the treatment these diseases and/or pharmacological tools for their study. A screening campaign of an in-house adenine derivative library revealed th at some compounds are able to inhibit the CK1δ enzyme isoform with IC50 in the low µM range. Molecular docking analyses were performed at a X-ray structure of the enzyme, leading to the rational design of novel di- and tri-substituted adenines that were synthesized and characterized. Biological e...
Source: Medicinal Chemistry Research - February 28, 2024 Category: Chemistry Source Type: research
Development of novel chalcone derivatives as multifunctional agents for the treatment of Alzheimer ’s disease
AbstractTo develop multifunctional agents for the treatment of Alzheimer ’s disease (AD), a series of novel chalcone derivatives was developed as the multitarget-directed ligands. Their MAOs inhibitory activities, anti-inflammation properties and neuroprotective effects were evaluated in vitro. The results showed that most of the synthetic compounds exhibited good sele ctive MAO-B inhibitory activity. Among them, compound3i exhibited the best MAO-B inhibitory potency with IC50 values of 0.092 μM, and the molecular docking provide possible mechanism for its high MAO-B inhibitory potency. Compound3i also significantly ...
Source: Medicinal Chemistry Research - February 26, 2024 Category: Chemistry Source Type: research
2-Styrylchromones as inhibitors of α-amylase and α-glucosidase enzymes for the management of type 2 diabetes mellitus
Abstractα-amylase and α-glucosidase are key enzymes implicated in carbohydrate digestion and their inhibition has been suggested as a powerful approach for regulating blood glucose levels. The present work describes for the first time their inhibition by a group of twelve hydroxylated 2-styrylchromones (2 -SC). Our findings revealed that 2-SC display strong systematic inhibition of α-glucosidase rather than α-amylase activity. The number and position of the hydroxy groups in the chromone moiety further modulate the inhibitory profile of the studied compounds, and the derivatives bearing one catecho l unit are efficient...
Source: Medicinal Chemistry Research - February 24, 2024 Category: Chemistry Source Type: research
Synthesis and pharmacological activities of Schiff bases with some transition metal complexes: a review
AbstractSchiff bases transition metal complexes have received significant attentions in the scientific community for their versatile applications. The incorporation of metals to Schiff base ligands attracts much attention, since the metals and Schiff base ligands coordinated via bonding. Thus, chelation effects will enhance and improve the biological activities of the derivatives of title compound. Most of these derivatives displayed broad range bioactivities including antibacterial, antifungal, antituberclosis, antimalarial, antioxidant, antidiabetic, anti-inflammatory and anticancer activities. Up to date, continuous eff...
Source: Medicinal Chemistry Research - February 19, 2024 Category: Chemistry Source Type: research
The use of single-molecule FRET for the characterization of Holliday junctions containing human telomeric DNA: a methodological approach for nanoscale distance, mobility, and stability measurements
We describe in detail the setup and optimization of the single-molecule fluorescence microscope, along with data acquisition and analysis procedures. Furthermore, we address potential challenges and provide troubleshooting strategies to ensure successful d ata collection and interpretation. The presented methodology serves as a valuable resource for researchers aiming to employ smFRET to study Holliday junctions and other biomolecular systems at the nanoscale, paving the way for further advancements in the field of single-molecule biophysics. (Source: Medicinal Chemistry Research)
Source: Medicinal Chemistry Research - February 19, 2024 Category: Chemistry Source Type: research
Synthesis, characterization, and anticancer activity of syringaldehyde-derived chalcones against female cancers
AbstractA series of novel chalcone analogs derived from syringaldehyde have been synthesized through acid or base-catalyzed aldol condensation. The anticancer activity of the newly synthesized compounds was assessed against a range of women-specific cancer cell lines, including A2780 (ovarian cancer), HeLa and C33a (cervical cancer), and MDA-MB-453, MDA-MB-231 and MCF-7 (breast cancer). The majority of these compounds demonstrated remarkable cytotoxicity against the tested cancer cells. Compound2a displayed the most promising anti-proliferation activity against the selected female cancer cells, while also exhibiting the we...
Source: Medicinal Chemistry Research - February 19, 2024 Category: Chemistry Source Type: research
Targeting disease with benzoxazoles: a comprehensive review of recent developments
AbstractBenzoxazole is an attractive scaffold in medicinal chemistry due to its diverse biological applications. From 2016 to 2023, a plethora of benzoxazole derivatives have been synthesized and evaluated for their pharmacological activities but a review on this topic was found lacking. This review thus aims to fill the gap and discusses the pharmacological activities of the synthesized derivatives, emphasizing their interactions with key biological targets implicated in diseases such as cancer, diabetes, pain, inflammation, and cardiovascular disorders. Relevant works were selected mainly from databases such as PubMed an...
Source: Medicinal Chemistry Research - February 18, 2024 Category: Chemistry Source Type: research
Preliminary structure −activity relationships analysis on N-(3,5-dichlorophenyl)-4,5-dihydronaphtho[1,2-d]thiazol-2-amine, a disruptor of mycobacterial energetics
AbstractThe increasing emergence of drug-resistance among mycobacteria represents a serious global health threat, requiring novel and effective therapeutic strategies. The lack of innovation in the drug discovery approach and/or in the combination of the therapeutic cocktail makes inevitable the onset of resistance also for the newly marketed drugs such as bedaquiline and delamanid. Therefore, different therapeutic tools are urgently required. Adjuvant therapies (AT), that is those approaches aimed at boosting the existing treatment, rather than replacing it with another, have gained increasing consideration in the antibac...
Source: Medicinal Chemistry Research - February 17, 2024 Category: Chemistry Source Type: research
Insights on synthetic strategies and structure-activity relationship of donepezil and its derivatives
AbstractThis comprehensive review focuses on the synthesis and derivatives of donepezil, a pivotal Alzheimer ’s disease (AD) medication introduced in 1997. As a selective acetylcholinesterase inhibitor with 100% oral bioavailability and a 70-h half-life, donepezil’s success in neurodegenerative disorder management has spurred extensive research into its synthesis and structural modifications. The revie w examines diverse synthetic approaches, evaluating their efficiency, cost, toxicity, and scalability. Methods range from traditional hazardous chemicals to eco-friendly strategies. Structural modifications and their imp...
Source: Medicinal Chemistry Research - February 17, 2024 Category: Chemistry Source Type: research
Identification of novel benzoyl hydrazine derivatives as activators of neddylation pathway to inhibit the tumor progression in vitro
AbstractNeddylation modification is frequently overexpressed in many types of human tumors. As a result, targeting neddylation pathway has been identified as viable anticancer therapeutic strategy. The NEDD8-activating enzyme (NAE) serves as a crucial role in a variety of cellular functions. Here, a new library of piperidine analogs was developed, produced and assessed for antiproliferative efficacy against A549, MGC-803, MCF-7KYSE-30 cell lines. The cell-based mechanistic studies showed thatIIb-10 bearing the benzoyl hydrazine motif can selectively inhibit the Neddylation modification of Cullin1 and Cullin3 by inhibiting ...
Source: Medicinal Chemistry Research - February 15, 2024 Category: Chemistry Source Type: research
Selectivity of N(2)-substituted oxotriazinoindole aldose reductase inhibitors is determined by the interaction pattern with Pro301-Arg312 loop of aldehyde reductase
AbstractNovel oxotriazinoindoles (OTIs) were recently reported as highly efficient and selective aldose reductase inhibitors. Here, a series of novelN(2)-substituted oxotriazinoindoles was developed with the aim to investigate molecular interactions within the aldose reductase (ALR2) inhibitor binding site. About twice increased inhibition efficacy of the most efficient derivative14 (N(2)-CH2CH2COOH) compared to the unsubstituted leadOTI was obtained, yet at the expense of selectivity relative to anti-target aldehyde reductase (ALR1). To explain the major drop in selectivity, observed also in otherN(2)-substituted derivati...
Source: Medicinal Chemistry Research - February 14, 2024 Category: Chemistry Source Type: research
