Medicinal Chemistry Research最新文献

A set of sesamol-derived acetamides was designed, synthesized, and evaluated against monoamine oxidases (MAO-A and MAO-B) and cholinesterases (AChE and BChE) for targeting neurodegenerative diseases. Most of the tested compounds showed inhibition activity at micromolar to nanomolar ranges. The 3,4-dichoro derivative (compound 19) was the most potent MAO-A inhibitor (IC₅₀ = 0.053 ± 0.001 µM) while the 4-methyl analog (compound 16) emerged as a lead MAO-B inhibitor (IC₅₀ = 0.019 ± 0.001 µM) compared to the reference inhibitors clorgyline (MAO-A IC₅₀ = 0.096 ± 0.003 µM) and selegyline (MAO B IC₅₀ = 0.021 ± 0.002 µM). Further, the 2,4-dichloro analog (compound 20) emerged as a potent dual MAO (MAO-A IC₅₀ = 0.160 ± 0.009 µM, MAO-B IC₅₀ = 0.071 ± 0.002 µM) and ChE (AChE IC₅₀ = 2.611 ± 0.086 µM and BChE IC₅₀ = 4.22 ± 0.162 µM) inhibitor. Moreover, molecular simulation studies revealed that H-bonding and hydrophobic interactions stabilize the virtual lead inhibitor-protein complex. Selected MAO-ChE inhibitors showed significant antioxidant and iron-chelation properties, suggesting their potential in treating neurological disorders characterized by impaired iron homeostasis. In summary, the structural modification attempted in the present study yielded a few nanomolar MAO (MAO-B) inhibitors and, thus, provided new insights into the linker requirements for dual MAO/ChE inhibitory properties.

Colorectal cancer is one of the most incident and lethal cancers in the world. The search for new compounds to treat this disease is being motivated by the occurrence of side effects and the rising in the resistance to chemotherapy. We synthesized a new class of conjugates bearing quinazolinone and melatonin which were prepared in good yields (63–93%) through one-pot three-component approach. quinazolinone/melatonin conjugates were proved against SW480 human colorectal adenocarcinoma cells and non-malignant colonic cells (NCM460). The cytotoxic and antiproliferative activities were determined through the sulforhodamine B assay. Compounds 1f, 1g and 1i–l displayed the best activity, being hybrids 1i–l the most selective against malignant cells, causing either a cytostatic and/or cytotoxic effect with evident morphological changes. Moreover, a theoretical drug-like/pharmacokinetics/toxicological study suggested that the hit-promising compounds 1i and 1j would have a great chance to advance to further preclinical studies as anti-cancer therapeutic candidate for oral oncological management. Our study evidently identified the potency of these quinazolinone/melatonin hybrids to be a prototype drug for further investigations toward novel therapeutics treatments of colorectal cancer.

A series of 8-(piperazin-1-yl)imidazo[1,2-a]pyrazine derivatives were designed and synthesized as acetylcholinesterase inhibitors (AChEIs) and antioxidants for the treatment of Alzheimer’s disease (AD). Moreover, the biological evaluation results demonstrated that these synthesized compounds exhibited moderate inhibitory activities toward acetylcholinesterase (AChE) and radical scavenging activities. Among them, compound 17r was the most potent AChE inhibitor with an IC₅₀ value of 0.47 μM and moderate inhibitory activity against butyrylcholinesterase (BuChE) (IC₅₀ = 11.02 μM). The selectivity index (SI) value of AChE over BuChE was 23.45, surpassing that of the reference drug galantamine (AChE IC₅₀ = 5.01 μM, BuChE IC₅₀ = 18.46 μM, SI = 3.68). Compound 17o had the best antioxidant activity with an IC₅₀ value of 89.33 μM, which was lower than that of ascorbic acid (IC₅₀ value = 25.70 μM) as the control drug. Furthermore, the results of molecular docking studies indicated that 17r could simultaneously bind to both catalytic active site and peripheral anionic site of AChE, which was consistent with the mixed inhibition pattern shown by enzyme kinetic studies. The interaction’s stability of 17r-AChE/BuChE were also assessed using a conventional atomistic 100 ns dynamics simulation study, which revealed the conformational stability of representative compound 17r in the cavity of the AChE. In addition, the molecular properties of all compounds were predicted online through the SwissADME, and the best active compound 17r matched the properties of most orally administered drugs. Based on the biological activity and molecular properties, compound 17r as AChEI was valuable for further development.

Anthocyanins are water-soluble naturally occurring flavonoids present in fruits, flowers, leaves, and roots of fruit plants and vegetables. One of the important anthocyanidin components of red wine and berries is delphinidin (DP). This review provides an update on the potential of DP in cancer therapy, with a further understanding of the mechanisms involved. Delphinidin has been shown to elicit inhibitory effects on catabolizing enzymes of human granulocytes and parasites, TNF-induced COX-2 expression in mouse epidermal cells, and reduce oxidative stress. It also inhibited anchorage-independent growth and caused cell death in breast cancer cell lines. Delphinidin increased Nrf2 expression, increased HO-1 production, and promoted mRNA expression of mitochondrial biogenesis-related factors. Further, DP has anti-proliferative and pro-apoptotic effects in various cancer cell lines such as lung, breast, and ovarian cancer cells. The mTOR-related pathway is the most important signaling pathway in the activation of autophagy, and DP has been shown to exert its cytotoxic effects on cancer cell lines via activating protein kinases. Among DP derivatives, delphinidin-3-O-glucoside has the best anticancer activity because it is easily absorbed. However, the metabolism of DP and its bioavailability in biological systems need to be explored to fully understand its benefits.

Menispermum dauricum DC (the moonseed family Menispermaceae) was used to treat various diseases, such as inflammatory disorders, and arrhythmia. Dauricine (DRC) is the principal bisbenzylisoquinoline alkaloid found in the roots of this medicinal plant. To date, there is still a lack of documents that review natural occurrence, and pharmacological and pharmacokinetic studies regarding this molecule. The current research tends to fill this gap. References have been systematically searched from the Web’s largest databases, such as Web of Science, Google Scholar, Sci-Finder, PubMed, and others, for relevant literature. The current review has also covered the pharmacological processes and mechanisms of the studied compound in a visible arrangement. DRC has possessed a great variety of in vitro and in vivo pharmacological activities, including anticancer, anti-inflammatory, and vasorelaxant, as well as protection to the brain, bone, and lungs. The underlying mechanisms relate to various signaling pathways, in which the NF-κB (nuclear factor kappa B) can be seen as the main route. Pharmacokinetic actions of DRC may relate to the loss of proton and methyl groups, and/or the addition of hydroxyl and sugar units, whereas its absolute bioavailability is found to be less than 50%. The other pharmacological assays are expected. More studies mentioning clinical experiments, toxicology, and bioavailability are encouraged. Structural modification is such a good approach to enhance pharmacological value and reduce toxicity

The worldwide rise in cancer incidence and mortality rates has spurred the search for new pathways implicated in cancer development and progression. One such target is glyoxalase 1 (GLO-I), a key player in methylglyoxal detoxification and a factor in the proliferation and prognosis of numerous cancers. Recent studies led by Al-Shar’i et al. utilized computer-aided drug design to identify potential inhibitors of GLO-I. The second most potent hit, (Z)-5-(5-((2,4-dioxothiazolidin-5-ylidene)methyl)furan-2-yl)-2-hydroxybenzoic acid, (IC₅₀ = 4.24 µM), was selected as a lead for further optimization. Through molecular docking, 27 analogs were designed and evaluated for binding affinity, with 14 of the top-scorings synthesized and tested for their inhibitory activity against GLO-I. The majority of these analogs showed enhanced activities relative to the lead compound, with the most potent having an IC₅₀ of 150 nM. These findings pave the way for the continued development of highly effective GLO-I inhibitors.