Medicinal Chemistry Research最新文献

The presence of neuronal amyloid β (Aβ) plaques and neurofibrillary tangles are the main indicators of Alzheimer’s disease (AD) and Parkinson’s disease (PD), which are the most common neurological diseases of old age. It is obvious that the existing and developed treatments are not able to change the conditions and cure these diseases, so the development of preventive therapeutic interventions without complications seems necessary. Clinical findings indicate that oxidative stress and neurotoxicity caused by amyloid β (Aβ) play a fundamental role in the pathogenesis of Alzheimer’s disease (AD). Among a wide range of medicinal compounds studied for the treatment and prevention of neurological diseases, Nobiletin (NOB)has been the focus of researchers. NOB is a bioflavonoid isolated from citrus peel that has anti-inflammatory, antioxidant and anti-dementia properties and the ability to improve intracellular and extracellular antibodies. In this study, the neuroprotective effects of NOB against Aβ-induced neurotoxicity discovered in the last decade were discussed. The molecular mechanisms involved have also been considered.

Numerous bone illnesses, including osteoporosis, are brought on by abnormal osteoclast differentiation. The identification of effective strategies for preventing osteoporosis involves focusing on the production and activation of osteoclasts. Herein, we synthesized a new series of tetrakisphosphonic acid derivatives and assessed their farnesyl pyrophosphate synthase inhibitory activity (FPPS) and anti-osteoclastogenic properties in vitro using the MTT assay and the Tartrate-Resistant Acid Phosphatase (TRAP) staining test. Among the synthesized novel tetrakisphosphonic acid derivatives, the unsubstituted benzylidene derivative 2a and the 2-brominated benzylidene derivative 2g exhibited the most promising bioactivity on the FPPS. All the synthesized compounds were proven to have the capacity to decrease the osteoclastogenesis process. Furthermore, both compounds 2a and 2g displayed the highest antiosteoclastogenic activity when compared to the reference compound, zoledronate. Molecular docking investigations revealed the probable interaction patterns between the potent derivatives 2a and 2g in the hFPPS binding pocket. The results of this investigation indicated that these novel compounds might be useful as FPPS-targeting and antiosteoclastogenic medications.

Human coronaviruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), pose a serious threat to human life and the global economy. To combat emerging viruses and virus variants, it is essential to develop antivirals with non-specific activities. In this study, we report on the synthesis and antiviral properties of four types of polysulfate-grafted maleimide-based enediyne (EDY) molecules. The sulfates in these EDY molecules are designed to target viruses through non-specific electrostatic interactions, providing extracellular viral targeting ability. Meanwhile, the core EDY generates radical species that disintegrate the viral structure proteins, thereby diminishing the infectivity of coronaviruses. Electron paramagnetic resonance spectroscopy confirmed the radical-generating property of enediynes, while antiviral experiments demonstrated that these enediynes exhibit antiviral activity down to micromolar concentrations, suggesting a promising future for this strategy in developing antiviral drugs.

FXIa has emerged as a promising therapeutic target for treating thrombotic diseases. With the aim to replace the aniline motif of asundexian with novel P2’ fragments, bicyclic isoquinoline and naphthalene rings were designed. The target compounds with isoquinoline ring were synthesized via 13 steps of chemical reactions. Substituents within the rings were investigated to elucidate the structural determinants governing selective or dual inhibition of FXIa and Plasma Kallikrein (PKa). In vitro testing showed that some of the designed compounds exhibited comparable potency against both FXIa and PKa, while others achieved up to 94-fold selectivity. Analysis of structure-activity relationships (SARs) uncovered the pivotal role of the carboxylic acid moiety in retaining inhibition of FXIa and PKa, and the steric hindrance and hydrogen-bond receptor functional groups were identified as key factors influencing the selectivity of FXIa inhibition over PKa. The docking study additionally unveiled different binding modes that play a significant role in the observed activity and selectivity. Furthermore, the selected compounds significantly extended the plasma coagulation time in a dose-dependent manner. Altogether, the bicyclic compounds may be promising lead compounds for the development of highly effective FXIa inhibitors.

New ellipticine analogs with indole cores were synthesized. and evaluated for their anticancer activity. A new compound, scaffolds, revealed broad-spectrum anticancer potential in one-dose and five doses screening. against the full 60-cell line at NCI. Compounds 2a and 3c had been selected for five-dose screening, where they showed marked anticancer activity against the tested cell lines with an average GI₅₀ (MG-MID) value of 2.23 and 0.98 mM, respectively. Compounds 2a, 2b, 2d, 3b, 3c, and 12 showed noted Topoisomerase Type IIβ inhibitory activity with inhibition records 85.45, 94.7, 93.5, 91.6, 89, and 94.5 percent, respectively. Molecular modeling studies and physicochemical parameter calculations of the most active compounds confirmed their safe. drug-like properties. as a promising anticancer class.

The COVID-19 pandemic has been a major reason behind the increased research aimed at the identification of effective antiviral agents. Among these, Nucleoside analogs have shown a promising effect on the inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus replication, the pathogen of COVID-19. Nucleoside analogs are synthetic compounds designed to mimic natural nucleosides, the building blocks of RNA and DNA. This review provides a comprehensive examination of the pivotal role nucleoside analogs play in combating SARS-CoV-2 infections. These analogs function by incorporating into the viral RNA during replication, disrupting the synthesis process and preventing the virus from proliferating. Researchers have identified multiple nucleoside analogs exhibiting robust antiviral efficacy against SARS-CoV-2, including remdesivir, favipiravir, and molnupiravir. This review explores the mechanisms of action, pharmacokinetics, and safety profiles of these nucleoside analogs. Furthermore, it discusses the challenges and limitations associated with their use, including the emergence of resistant viral strains and potential side effects. Additionally, the review delves into ongoing research efforts to optimize nucleoside analogs for enhanced efficacy and reduced adverse effects. In summary, the article aims to enhance our overall understanding of nucleoside-based treatments by combining information about their chemistry, mechanisms of action, and activation pathways. The goal is to contribute to advancements in addressing emerging viral threats in the future.

In this study, we present a series of 2-(5-chlorothiophen-2-yl)-1H-benzo-[d]-imidazol-2-yl)-6,7-dihydrobenzo-[d]-imidazo[2,1-b]thiazol-8(5H)-ones (7a–q) through a short, four-step process using readily available starting materials. The synthesis included crucial transformations such as the condensation of 1,3-cyclohexanediones with thiourea, cyclization with acetophenones, and the Vilsmeier-Haack-Arnold reaction. All the compounds were fully characterized and systematically screened for antibacterial, antifungal and antiviral activity. Among all, the compounds 7b (CC50: >1000 µM, IC50 = 4.8 µM, SI = > 63) and 7h (CC50: >1000 µM, IC50 = 5.6 µM, SI = > 54) with 3-methyl and 3-trifluoromethyl groups showed significant virus inhibitory activity against the pandemic influenza virus A/Puerto Rico/8/34 (H1N1) with high selectivity index values and favorable toxicity profiles. The compounds were also evaluated for antibacterial and antifungal activity, exhibited only moderate inhibition. Molecular docking studies have elucidated strong binding interactions with the viral target, the RNA polymerase PB1-PB2 subunits of influenza A virus. ADMET profiles highlighted encouraging drug-like properties and positioned 2-(5-chlorothiophen-2-yl)-1H-benzo-[d]-imidazol-2-yl)-6,7-dihydrobenzo-[d]-imidazo [2,1-b]thiazol-8(5H)-one as a promising candidate for further development as antiviral therapeutics.

A collection of 17 compounds comprising benzimidazole with a dihydroimidazobenzothiazole scaffolds were synthesized and evaluated against the pandemic influenza virus A/Puerto Rico/8/34 (H1N1); resulted two compounds with high selectivity index and favourable toxicity profile.

Multiple myeloma (MM) is an incurable hematological malignancy with increasing incidence and mortality rates, with a worldwide incidence of 160,000 cases per year. Currently approved treatments, including bortezomib treatment, have adverse effects that ultimately lead to the development of resistance. Inadequate vitamin D (VD) levels are frequently observed in patients with MM, and its supplementation has anti-proliferative effects on different MM phenotypes. However, the risk of hypercalcemia restricts the application of VD in cancer therapy; therefore, we analyzed truncated VD analogs with anticancer effects but no calcemic activity. We previously identified a derivative of the C/D ring fragment of vitamin D2 (VD2) against cervical cancer, lung cancer, and MM. Herein, we conducted a structure–activity relationship study by introducing more derivatives and testing them against different MM cells, including bortezomib-sensitive and bortezomib-resistant phenotypes. VDF-4 exhibited remarkable toxicity against all tested cells, with less of an effect on normal blood cells; this reflects its potentially high selectivity. VDF-4 IC₅₀ values against KMS-12-PE, KMS-11, and KMS-11/BTZ were 19.1 ± 1.0, 19.8 ± 2.5, and 23.3 ± 1.9 µM, respectively. Notably, the KMS-11/BTZ cells were insensitive to VD2. Furthermore, VDF-4 demonstrated moderate activity against other leukemic cell lines, including Jurkat and M8166 cells. Although its mechanism of action has not yet been elucidated, VDF-4 is a promising compound and warrants further investigation.

A series of bis-benzodioxole derivatives was designed, synthesized, and evaluated. These target compounds were designed through structure simplification and ester bond flipping. The lipid-lowering activity of these target compounds was preliminarily evaluated in a hyperlipidemic mouse model induced by Triton WR 1339. The results showed that piperonylic acid -6-(3,4-methylenedioxyphenoxy) hexyl ester (T5) possesses notable lipid-lowering properties, reducing triglyceride (TG) and total cholesterol (TC) levels. The dose-dependent study revealed that compound T5 decreased TG and TC more strongly with the increase of dose. It was observed that T5 had considerable effects on decreasing TG, TC and low density lipoprotein cholesterol (LDL-C) levels in hyperlipidemic mice induced by high fat diet (HFD). Meanwhile, T5 was found to have hepatoprotective activity, with the liver aspartate transaminase (AST) and alanine aminotransferase (ALT) significantly decreasing and histopathological observation showing that it inhibited lipids accumulation in the liver and alleviated liver injury. T5 has been shown to stimulate peroxisome proliferator-activated receptor-α (PPAR-α) and suppress hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase in the liver in connection to lipid metabolism. The molecular docking study also revealed that T5 has a high affinity for the active sites of PPAR-α and HMG-CoA reductase. Furthermore, other beneficial activities, including antioxidation and anti-inflammation, were also noted. It is possible that further exploration may result in compound T5 becoming a promising candidate for lipid-lowering therapy.