MedChemComm最新文献

Fusion inhibitor peptide (FIP), a short peptide known as a measles virus (MeV) infection inhibitor, inhibits membrane fusion between the viral envelope of MeV and the host cell membrane. Therefore, FIP is potentially useful as a drug candidate for treating MeV infection, but improvement of inhibitory activity is desirable. In this study, we conducted a structure–activity relationship study of FIP and, based on the result and the previously reported crystal structure of the complex, we designed FIP derivatives. From a series of derivatives, we discovered an FIP derivative with a strong inhibitory activity (IC₅₀ = 210 nM) derived from the enhanced binding affinity (K_D = 6.6 nM) to the MeV fusion protein.

Despite significant progress in drug discovery, there remains an urgent need to identify new structures capable of targeting drug-resistant diseases, as well as novel pathogens, to address the growing challenges in global health. This work highlights the underexplored potential of twistane-like structures as promising candidates for drug development, particularly as antiviral agents. We provide the first comprehensive study of their antiviral activity, in particular against SARS-CoV-2. We report the synthesis of a family of chiral indolyl-twistenediones, with the separation and characterization of both enantiomers via chiral semipreparative HPLC. The absolute configurations were determined using experimental and theoretical ECD techniques, supported by DFT calculations. A detailed biological study of their antiviral activity against various pathogenic RNA viruses demonstrates selective efficacy against members of the Coronaviridae family, specifically targeting a post-entry step in the viral replication cycle. Further investigation revealed a remarkable chiral distinction in the antiviral activity between the two enantiomers, opening new avenues for research in the 3D space of chiral cage compounds.

Stimuli-responsive smart materials for biomedical applications have gained significant attention because of their potential for selectivity and sensitivity in biological systems. Even though ample stimuli-responsive materials are available, the use of traditional Ayurvedic compounds in the fabrication of pharmaceuticals is limited. Among various materials, gels are one of the essential classes because of their molecular-level tunability with little effort from the environment. In this study, we report a simple synthesis method for multifunctional glycolipids using a starting material derived from biologically significant natural molecules and carbohydrates in good yields. The synthesized glycolipids were prone to form a hydrogel by creating a 3D fibrous architecture. The mechanism of bottom-up assembly involving the molecular-level interaction was studied in detail using SEM, XRD, FTIR, and NMR spectroscopy. The stability, processability, and thixotropic behavior of the hydrogel were investigated through rheological measurements, and it was identified to be more suitable for biomedical applications. To evaluate the potential application of the self-assembled hydrogel in the field of medicine, we encapsulated a natural drug, curcumin, into a gel and studied its pH as a stimuli-responsive release profile. Interestingly, the encapsulated drug was released both in acidic and basic pH levels at a different rate, as identified using UV-vis spectroscopy. It is worth mentioning that the gelator used for fabricating smart soft materials displays significant potential in selectively compacting the biofilm formed by Streptococcus pneumoniae. We believe that the reported multifunctional hydrogel derived from bhilawanol-based glycolipid holds great promise in medicine.

Renin–angiotensin–aldosterone system (RAAS) is crucial in cardiovascular homeostasis. Any disruption in this homeostasis often leads to numerous cardiovascular diseases (CVDs) and non-cardiovascular diseases. Small molecules that show ability toward mechanically modulating RAAS components have been developed to address this problem, thus providing opportunities for innovative drug discovery and development. This review is put forth to provide a comprehensive understanding not only on the signaling mechanisms of RAAS that lead to cardiovascular events but also on the use of small molecules targeting the modulation of RAAS components. Further, the detailed descriptions of the drugs affecting the RAAS and their pharmacodynamics, kinetics, and metabolism profiles are provided. This article also covers the limitations of the present therapeutic armory, followed by their mechanistic insights. A brief discussion is offered on the analysis of the chemical space parameters of the drugs affecting RAAS compared to other cardiovascular and renal categories of medications approved by the US FDA. This review provides structural insights and emphasizes the importance of integrating the current therapeutic regimen with pharmacological tactics to accelerate the development of new therapeutics targeting the RAAS components for improved and efficacious cardiovascular outcomes. Finally, chemical spacing parameters of RAAS modulators are provided, which will help in understanding their peculiarities in modulating the RAAS signaling through structural and functional analyses. Furthermore, this review will assist medicinal chemists working in this field in developing better drug regimens with improved selectivity and efficacy.

Anti-infective hydrogel is an emerging and innovative material used as an antibacterial ointment or to coat medical devices. Here, we synthesized a novel derivative of N-glycidyl D-tryptophan ether using the D-isoform of tryptophan through a ring-opening polymerization reaction. The compound was characterized using gel permeation chromatography (GPC), HPLC, ¹H NMR, ¹³C NMR, MALDI-TOF-MS, and FTIR spectroscopy. The results demonstrated its antibacterial activity by inhibiting quorum sensing and subsequent biofilm formation. In vivo studies revealed the ability of the compound to promote wound healing by reducing inflammatory cytokine levels, such as tumor necrosis factor alpha, interleukin-1β, and IL-6. Moreover, the compound showed antioxidant activity by scavenging the DPPH radical due to the presence of polymeric hydroxyl acidic protons near the nitrogen. Since inflammation prompted ROS-initiated DNA strand breaks, it was also confirmed that the compound could reduce DNA strand break accumulation, as demonstrated through testing against bleomycin-induced DNA strand break accumulation. Therefore, the synthesized compound, which could be used as a base material for ointments, was found to be effective for antibacterial and wound healing actions by (a) inhibiting biofilm formation by bacteria, (b) reducing the expression of inflammatory cytokines, and (c) preventing the accumulation of DNA strand breaks through free-radical scavenging activity.

Resistance of oestrogen receptor-positive (ER+) breast cancer, the most prevalent type of breast cancer accounting for ∼70% of all cases, to current therapies necessitates the study of alternative strategies. One promising strategy is the multi-targeting approach using dual aromatase-steroid sulfatase inhibitors (DASIs). Herein, we describe the development of DASIs using a common benzofuran pharmacophore. Triazole benzofuran sulfamates were found to have low nM aromatase (Arom) inhibitory activity but no steroid sulfatase (STS) inhibitory activity (IC₅₀ > 10 μM); by contrast, benzofuran ketone sulfamates demonstrated low nM STS inhibitory activity but no Arom inhibitory activity (IC₅₀ > 1 μM). The addition of a methyl group at the 3rd position of the benzofuran ring in the benzofuran ketone sulfamate 19 (R¹ = CH₃) had a notable effect, resulting in dual aromatase and STS inhibitory activities with the 4-chloro derivative 19b (Arom IC₅₀ = 137 nM, STS IC₅₀ = 48 nM) and 4-methoxy derivative 19e (Arom IC₅₀ = 35 nM, STS IC₅₀ = 164 nM) optimal for dual inhibition. Arom/STS inhibition results combined with molecular dynamics studies provided a clear rationale for the activity observed.

Unveiling novel pathways for drug discovery forms the foundation of a new era in the combat against tuberculosis. The discovery of a novel drug, bedaquiline, targeting mycobacterial ATP synthase highlighted the targetability of the energy metabolism pathway. The significant potency of bedaquiline against heterogeneous population of Mycobacterium tuberculosis marks ATP synthase as an important complex of the electron transport chain. This review focuses on the importance and unique characteristics of mycobacterial ATP synthase. Understanding these distinctions enables the targeting of ATP synthase subunits for drug discovery, without aiming at the mammalian counterpart. Furthermore, a brief comparison of the structural differences between mycobacterial and mitochondrial ATP synthase is discussed. Being a complex multi-subunit protein, ATP synthase offers multiple sites for potential inhibitors, including the a, c, ε, γ, and δ subunits. Inhibitors targeting these subunits are critically reviewed, providing insight into the design of better and more potent chemical entities with the potential for effective treatment regimens.

Piglets afflicted with porcine epidemic diarrhea virus (PEDV) experience severe diarrhea and elevated death rates, leading to substantial financial losses in the pig farming sector. The objective of this study is to investigate the impact of saponins on PEDV within Vero cells by utilizing different methodologies to evaluate their anti-PEDV effect. By producing 40 saponins, we have discovered that No. 29, No. 31, No. 35, and No. 38 exhibit properties that make them effective against PEDV, serving as potential drugs. The findings showed that in a clear dose-dependent manner, the mRNA levels of PEDV were significantly inhibited in the high, middle, and low-dose groups of No. 29, No. 31, No. 35, and No. 38, when compared to the PEDV control. The four tested saponins significantly inhibited the levels of PEDV N contents and viral titers. Furthermore, concentration of cytotoxicity 50% (CC₅₀) values for No. 29, No. 31, No. 35, and No. 38 saponins were 37.13 μM, 52.86 μM, 44.98 μM, and 43.81 μM, respectively, demonstrating the safety of these medications in clinical environments. Collectively, these findings indicate that the four examined saponins could efficiently modulate the immune response against PEDV and hold promise for utilization in antiviral treatments.

In continuation of our efforts to develop new anticancer compounds, a new series of imidazo[1,5-a]pyridine-chalcone derivatives was designed, synthesized, characterized, and evaluated for its cytotoxicity against five human cancer cell lines, i.e., breast (MDA-MB-231), colon (RKO), bone (Mg-63), prostate (PC-3), and liver (HepG2) cell lines, as well as a normal cell line (HEK). Among the synthesized compounds, two exhibited promising cytotoxicity against the MDA-MB-231 cell line with IC₅₀ values of 4.23 ± 0.25 μM and 3.26 ± 0.56 μM. We also studied apoptotic induction of the compounds using annexin V-FITC/PI staining, and ROS-mediated mitochondrial damage was elucidated using DCFDA, followed by JC-1 staining. The potential activity of the compounds was further confirmed by immuno-fluorescence and molecular docking studies, which revealed the anticancer activity of active compounds through binding and microtubule disruption.

Aberrant protein misfolding and accumulation is considered to be a major pathological pillar of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Aggregation of amyloid-β (Aβ) peptide leads to the formation of toxic amyloid fibrils and is associated with cognitive dysfunction and memory loss in Alzheimer's disease (AD). Designing molecules that inhibit amyloid aggregation seems to be a rational approach to AD drug development. Over the years, researchers have utilized a variety of therapeutic strategies targeting different pathways, extensively studying peptide-based approaches to understand AD pathology and demonstrate their efficacy against Aβ aggregation. This review highlights rationally designed peptide/mimetics, including structure-based peptides, metal-peptide chelators, stapled peptides, and peptide-based nanomaterials as potential amyloid inhibitors.