MedChemComm最新文献

Globally, the emergence of anti-microbial resistance in pathogens has become a serious threat to human health and well-being. Infections caused by drug-resistant microorganisms in hospitals are associated with increased morbidity, mortality, and healthcare costs. Acinetobacter baumannii is a Gram-negative bacterium belonging to the ESKAPE group and is widely associated with nosocomial infections. It persists in hospitals and survives antibiotic treatment, prompting acute infections such as urinary tract infections, pneumonia, bacteremia, meningitis, and wound-related infections. An innovation void in drug discovery and the lack of new therapeutic measures against A. baumannii continue to afflict infection control against the rising drug-resistant cases. The emergence of drug-resistant A. baumannii strains has also led to the incessant collapse of newly discovered antibiotics. Therefore exploring novel strategies is requisite to give impetus to A. baumannii drug discovery. The present review discusses the bacterial research community's efforts in the field of A. baumannii, focusing on the strategies adapted to identify potent scaffolds and novel targets to bolster and diversify the chemical space available for drug discovery. Firstly, we have discussed existing chemotherapy and various anti-microbial resistance mechanisms in A. baumannii bacterial strains. Next, we elaborate on multidisciplinary approaches and strategies that may be the way forward to combat the current menace caused by the drug-resistant A. baumannii strains. The review highlights the recent advances in drug discovery, including combinational therapy, high-throughput screening, drug repurposing, nanotechnology, and anti-microbial peptides, which are imperative tools to fight bacterial pathogens in the future.

We report the characterization of potent and selective ROCK inhibitors identified through a core-hopping strategy. A virtual screening workflow, combining ligand- and structure-based methods, was applied on a known series of ROCK inhibitors bearing an acetamido-thiazole scaffold. The most promising replacement of the central core was represented by a benzoazepinone ring, which was selected as a starting point for a subsequent chemical exploration. The overall design approach exploited previous SARs available for congeneric series and crystallographic information to optimize the hinge-binding group as well as the terminal aromatic moiety interacting with the glycine-rich loop. The introduction of elongated and flexible charged groups led to compound 15, which exhibited sub-nanomolar potencies in biochemical and cellular assays, as well as a remarkable selectivity over PKA. HDX studies not only supported the postulated binding mode of compound 15 but also confirmed the crucial role of specific ROCK peptide segments in driving ligand selectivity.

Targeting the prostate-specific membrane antigen (PSMA) with radiopharmaceuticals for imaging and/or therapy has demonstrated significant advancement in the management of prostate cancer patients. However, PSMA targeting remains unsuccessful in prostate cancers with low expression of PSMA, which account for 15% of cases. The neurotensin receptor-1 (NTS₁) has been highlighted as a suitable oncotarget for imaging and therapy of PSMA-negative prostate cancer lesions. Therefore, heterobivalent probes targeting both PSMA and NTS₁ could improve the prostate cancer management. Herein, we report the development of a branched hybrid probe (JMV 7489) designed to target PSMA and/or NTS₁ bearing relevant pharmacophores and DOTA as the chelating agent. The new ligand was synthesized with a hybrid approach, which includes both syntheses in batch and in the solid phase. Saturation binding experiments were next performed on HT-29 and PC3-PIP cells to derive K_d and B_max values. On the PC3-PIP cells, [⁶⁸Ga]Ga-JMV 7489 displayed good affinity towards PSMA (K_d = 53 ± 17 nM; B_max = 1393 ± 29 fmol/10⁶ cells) in the same range as the corresponding reference monomer. A lower affinity value towards NTS₁ was depicted (K_d = 157 ± 71 nM; B_max = 241 ± 42 fmol/10⁶ cells on PC3-PIP cells; K_d = 246 ± 1 nM; B_max = 151 ± 44 fmol/10⁶ cells on HT-29 cells) and, surprisingly, it was also the case for the corresponding monomer [⁶⁸Ga]Ga-JMV 7089. These results indicate that the DOTA macrocycle and the linker are critical elements to design heterobivalent probes targeting PSMA and NTS₁ with high affinity towards NTS₁.

In the quest to identify new anti-Alzheimer agents, we employed drug repositioning or drug repositioning techniques on approved USFDA small molecules. Herein, we report the structure-based virtual screening (SBVS) of 1880 USFDA-approved drugs. The in silico-based identification was followed by calculating Prime MMGB-SA binding energy and molecular dynamics simulation studies. The cumulative analysis led to identifying domperidone as an identified hit. Domperidone was further corroborated in vitro using anticholinesterase-based assessment, keeping donepezil as a positive control. The analysis revealed that the identified lead (domperidone) could induce an inhibitory effect on AChE in a dose-dependent manner with an IC₅₀ of 3.67 μM as compared to donepezil, which exhibited an IC₅₀ of 1.37 μM. However, as domperidone is known to have poor BBB permeability, we rationally proposed new analogues utilizing the principles of bioisosterism. The bioisostere-clubbed analogues were found to have better BBB permeability, affinity, and stability within the catalytic domain of AChE via molecular docking and dynamics studies. The proposed bioisosteres may be synthesized in the future. They may plausibly be explored for their implication in the developmental progress of new anti-Alzheimer agent achieved via repurposing techniques in future.

Due to its essential roles in cell proliferation and apoptosis, the precise regulation of the Hippo pathway through LATS presents a viable biological target for developing new drugs for cancer and regenerative diseases. However, currently available probes for selective and highly drug-like inhibition of LATS require further improvement in terms of both activity, selectivity and drug-like properties. Through scaffold hopping aided by docking studies and AI-assisted prediction of metabolic stabilities, we successfully identified an advanced LATS inhibitor demonstrating potent kinase activity, exceptional selectivity against other kinases, and superior oral pharmacokinetic profiles.

NAFLD/NASH has emerged as a global health concern with no FDA-approved treatment, necessitating the exploration of novel therapeutic elements for NASH. Probiotics are known as an important adjunct therapy in NASH. Zbiotics (ZB183) is the first commercially available genetically engineered probiotic. Herein, we aimed to evaluate the potential therapeutic effects of Zbiotics administration on NASH management by modulating the cGAS-STING-signaling pathway-related RNA network. In silico data analysis was performed and three DEGs (MAPK3/EDN1/TNF) were selected with their epigenetic modulators (miR-6888-5p miRNA, and lncRNA RABGAP1L-DT-206). The experimental design included NASH induction with an HSHF diet in Wistar rats and Zbiotics administration in NASH rats in comparison to statin treatment. Liver functions and lipid profile were assessed. Additionally, the expression levels of the constructed molecular network were assessed using RT-PCR. Moreover, the Zbiotics effects in NASH were further validated with histopathological examination of liver and colon samples. Also, immunohistochemistry staining of hepatic TNF-α and colonic occludin was assessed. Oral administration of Zbiotics for four weeks downregulated the expression of the cGAS-STING-related network (MAPK3/EDN1/TNF/miR-6888-5p miRNA/lncRNA RABGAP1L-DT-206) in NASH models. Zbiotics also ameliorated hepatic inflammation and steatosis, as evidenced by a notable improvement in NAS score and decreased hepatic TNF-α levels. Furthermore, Zbiotics exhibited favorable effects on colon health, including increased crypt length, reduced inflammatory cell infiltration, and restoration of colonic mucosa occludin expression. In conclusion, our findings suggest that Zbiotics has potential therapeutic effects on NASH via modulating the gut–liver axis and the cGAS-STING signaling pathway.

A smart dendritic cell (DC)-derived whole cell cytokine (DWC) nano-regulator of TCPs was developed for tumor cytokine-immunotherapy. The DWCs were purified from activated DC-cultured media and applied as a nano-dosage form. It was found that TCPs could remodel extracellular matrices via the elimination of fibronectin and type I collagen (Col-I) in tumor tissues, as well as the inhibition of α-SMA expression in cancer associated fibroblasts (CAFs). Furthermore, after local TCP treatment, significant tumor inhibition could be achieved combined with radiotherapy.

A new series of potential flutamide-like antiandrogens has been designed and synthesized to treat prostate cancer. This new series results from our research, which has been aimed at discovering new compounds that can be used for androgen deprivation treatment. The antiandrogens were designed and synthesized by varying the acyl part, linker, and substitution of the benzene ring in the 4-nitro-3-trifluoromethylanilide scaffold of non-steroidal androgens. In addition, the characteristic feature of the nitro group was replaced by a boronic acid functionality. Compound 9a was found to be more effective against LAPC-4 than the standard antiandrogens flutamide, hydroxyflutamide, and bicalutamide. Moreover, it exhibited lower toxicity against the non-cancerous cell line HK-2. The initial in silico study did not show evidence of covalent bonding to the androgen receptor, which was confirmed by an NMR binding experiment with arginine methyl ester. The structure–activity relationships discovered in this study could provide directions for further research on non-steroidal antiandrogens.

Copper(II) and zinc(II) complexes with lapachol (HLap) of the composition [M(Lap)₂(N–N)] and [Cu(Lap)(H₂O)(terpy)]NO₃ (4), where M = Cu (1–3) or Zn (for 5–7), and N–N stands for bathophenanthroline (1 and 5), 5-methyl-1,10-phenanthroline (2 and 6), 2,2′-bipyridine (3), 2,2′;6′,2′′-terpyridine (terpy, 4) and 1,10-phenanthroline (7), were synthesised and characterised. Complexes 1–5 revealed strong in vitro antiproliferative effects against A2780, A2780R, MCF-7, PC-3, A549 and HOS human cancer lines and MRC-5 normal cells, with IC₅₀ values above 0.5 μM, and reasonable selectivity index (SI), with SI > 3.8 for IC₅₀(MRC-5)/IC₅₀(A2780). Considerable time-dependent cytotoxicity in A2780 cells was observed for complexes 6 and 7, with IC₅₀ > 50 μM (24 h) to ca. 4 μM (48 h). Cellular effects of complexes 1, 5 and 7 in A2780 cells were investigated by flow cytometry revealing that the most cytotoxic complexes (1 and 5) significantly perturbed the mitochondrial membrane potential and the interaction with mitochondrial metabolism followed by the triggering of the intracellular pathway of apoptosis.

Despite Hsp90's well documented promise as a target for developing cancer chemotherapeutics, its inhibitors have struggled to progress through clinical trials. This is, in part, attributed to the cytoprotective compensatory heat shock response (HSR) stimulated through intracellular Hsp90 inhibition. Beyond its intracellular role, secreted extracellular Hsp90 (eHsp90) interacts with numerous pro-oncogenic extracellular clients. This includes fibronectin, which in the tumour microenvironment enhances cell invasiveness and metastasis. Through the rational modification of known Hsp90 inhibitors (SNX2112 and SNX25a) we developed four Hsp90 inhibitory compounds, whose alterations restricted their interaction with intracellular Hsp90 and did not stimulate the HSR. Two of the modified cohort (compounds 10 and 11) were able to disrupt the assembly of the extracellular fibronectin network at non-cytotoxic concentrations, and thus represent promising new tool compounds for studying the druggability of eHsp90 as a target for inhibition of tumour invasiveness and metastasis.