Dysregulation of choline phospholipid metabolism and overexpression of phosphatidylcholine-specific phospholipase C (PC-PLC) is implicated in various cancers. Current known enzyme inhibitors include compounds based on a 2-morpholino-5--benzylamino benzoic acid, or hydroxamic acid, scaffold. In this work, 81 compounds were made by modifying this core structure to explore the pharmacophore. Specifically, these novel compounds result from changes to the central ring substitution pattern, alkyl heterocycle and methylation of the -benzyl bridge. The anti-proliferative activity of the synthesised compounds was assessed against cancer cell lines MDA-MB-231 and HCT116. PC-PLC enzyme inhibition was also assessed, and the development of a pharmacokinetic profile was initiated using a microsomal stability assay. The findings confirmed the optimal pharmacophore as a 2-morpholino-5--benzylamino benzoic acid, or acid derivative, scaffold, and that this family of molecules demonstrate a high degree of stability following treatment with rat microsomes. Additionally, benzylic -methylated compounds were the most biologically active compounds, encouraging further investigation into this region of the pharmacophore.

Degrons are short amino acid sequences that can facilitate the degradation of protein substrates. They can be classified as either ubiquitin-dependent or -independent based on their interactions with the ubiquitin proteasome system (UPS). These amino acid sequences are often found in exposed regions of proteins serving as either a tethering point for an interaction with an E3 ligase or initiating signaling for the direct degradation of the protein. Recent advancements in the protein degradation field have shown the therapeutic potential of both classes of degrons through leveraging their degradative effects to engage specific protein targets. This review explores what targeted protein degradation applications degrons can be used in and how they have inspired new degrader technology to target a wide variety of protein substrates.

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 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.

The sphingosine-1-phosphate-5 (S1P) receptor is one of the five membrane G protein-coupled receptors that are activated by the lysophospholipid, sphingosine-1-phosphate, resulting in regulation of many cellular processes. S1P receptors are located on oligodendrocytes and are proposed to influence oligodendrocyte physiology. Understanding S1P modulation during processes such as remyelination could have potential applications for demyelinating CNS disorders such as multiple sclerosis (MS). Herein, we report the synthesis and preliminary evaluation of a series of fluorinated 6-arylaminobenzamides as positron emission tomography (PET) ligands of S1P. Pharmacokinetic screening and binding evaluation using a [S]GTPγS assay led to the discovery of TEFM78, a selective and high affinity agonist of S1P. Radiosynthesis of [F]TEFM78 allowed pilot PET imaging studies in an animal model, which showed that [F]TEFM78 can cross the blood brain barrier with good uptake in rat brain and spinal cord.

In continuation of our efforts to develop new anticancer compounds, a new series of imidazo[1,5-]pyridine-chalcone derivatives was designed, synthesized, characterized, and evaluated for its cytotoxicity against five human cancer cell lines, , 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 IC 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.

In this work, we developed potential multifunctional agents to combat Alzheimer's disease. According to our strategy, fragments of tacrine and donepezil were merged in a unique hybrid structure. After successfully synthesizing the compounds, they were evaluated for their dual AChE/BuChE inhibitor potential and neuroprotector response using a glutamate-induced excitotoxicity model. Most of the compounds showed promising activity. Among them, the hybrid with 2,5-dimetoxysubstitution (3b) was the most potent analogue, triggering dual potent AChE/BuChE inhibition with low nanomolar affinity (IC ∼ 300 nM) and low toxicity to human liver cancer cells (HepG2). This analogue prevented the glutamate excitotoxic stimulus during pre/post treatment testing, maintained ATP levels, possessed an astrocytic protective response, and abolished the glutamate-induced excitotoxicity. Besides, the hit compound 3b exhibited suitable permeability in the blood-brain barrier (BBB) and low degradability in human blood-plasma. In addition, the docking studies suggested that the neuroprotectant response exhibited by 3b can be related to the direct blockage of the NMDA channel pore. Finally, an ideal neuropharmacokinetic profile was estimated for 3b. Overall, the designed conjugates provide a novel multifunctional molecular scaffold that can be used as a prototype drug in further investigations toward novel multipotent therapeutics for treating AD.

The development and characterization of quaternary phosphonium compounds (QPCs) have long benefitted from their incorporation into a cornerstone reaction in organic synthesis - the Wittig reaction. These structures have, more recently, been developed into a wide variety of novel applications, ranging from phase transfer catalysis to mitochondrial targeting. Importantly, their antimicrobial action has demonstrated great promise against a wide variety of bacteria. This review aims to provide an overview of recent development in non-polymeric biocidal QPC structures, highlighting their synthetic preparation, and comparing their antimicrobial performance. Discussions of similarities and dissimilarities to QACs are included, both in bioactivity as well as likely mechanism(s) of action. The observed potential of QPCs to eradicate Gram-negative pathogens a novel mechanism is highlighted, as there is an urgent need to address the declining biocide arsenal in modern infection control.

Novel thiazole analogs 3a, 3b, 4, 5, 6a-g, 8a, 8b, 9a-c, 10a-d and 11 were designed and synthesized as molecular mimetics of sunitinib. antitumor activity of the obtained compounds was investigated against HepG2, HCT-116, MCF-7, HeP-2 and HeLa cancer cell lines. The obtained data showed that compounds 3b and 10c are the most potent members toward HepG2, HCT-116, MCF-7 and HeLa cells. Moreover, compounds 3a, 3b, 6g, 8a and 10c were assessed for their VEGFR-2 inhibitory activity. Results proved that compound 10c exhibited outstanding VEGFR-2 inhibition (IC = 0.104 μM) compared to sunitinib. Compound 10c paused the G0-G1 phase of the cell cycle in HCT-116 and MCF-7 cells and the S phase in HeLa cells. Additionally, compound 10c elevated caspase-3/9 levels in HCT-116 and HeLa cells, leading to cancer cell death apoptosis. Furthermore, compound 10c showed a significant reduction in tumor volume in Swiss albino female mice as an breast cancer model. Docking results confirmed the tight binding interactions of compound 10c with the VEGFR-2 binding site, with its binding energy surpassing that of sunitinib. PK studies predicted compound 10c to have good oral bioavailability and a good drug score with low human toxicity risks.

Small molecules targeting activating mutations within the epidermal growth factor receptor (EGFR) are efficacious anticancer agents, particularly in non-small cell lung cancer (NSCLC). Among these, lazertinib, a third-generation tyrosine kinase inhibitor (TKI), has recently gained FDA approval for use in combination with amivantamab, a dual EGFR/MET-targeting monoclonal antibody. This review delves into the discovery and development of lazertinib underscoring the improvements in medicinal chemistry properties, especially in comparison with osimertinib. Analysis of its structure-activity relationships (SAR), as outlined in the patent literature, reveals the structural diversity explored enroute to the candidate molecule. The resulting structure of lazertinib is distinguished among other TKIs due to the combination of the hydrophobic phenyl and hydrophilic amine substituents on the pyrazole. The structural basis for the selectivity against the T790M mutation is enabled by the substituted pyrazole moiety, which facilitates both van der Waals and H-bonding interactions with the EGFR kinase domain. Insights from this case study offer lessons that can inform the future design of kinase inhibitors with improved safety and efficacy profiles for cancer treatment and other diseases.

Prodrugs are masked drugs that first become pharmacologically active after undergoing a structural change . They are designed to improve physicochemical/biopharmaceutical drug properties and increase site specificity. The prodrug approach is important when developing brain-targeting drugs due to the presence of the brain barriers that seriously limit the brain entry of highly polar, multifunctional drug entities. While several excellent reviews summarize the structural modifications facilitating transport across the brain barriers, a summary of mechanisms used for the activation of the prodrug in the brain is missing. Given the high need for innovative discoveries in brain drug development, we here review the most important tools being developed since 2000 for CNS prodrug activation.

Hypoxia is a hallmark of the glioblastoma multiforme microenvironment and represents a promising therapeutic target for cancer treatment. Herein, we report nitroaromatic-based triazene prodrugs designed for selective activation by tumoral endogenous reductases and release of the cytotoxic methyldiazonium ion a self-immolative mechanism. While compounds bearing a 2-nitrofuran bioreductive group were more efficiently activated by nitroreductases, 4-nitrobenzyl prodrugs 1b, 1d and 1e elicited a more pronounced cytotoxic effect against LN-229 and U-87 MG glioblastoma cell lines under hypoxic conditions when compared to temozolomide (TMZ), the golden standard for glioblastoma treatment. This cytotoxic response aligns with the increased apoptosis levels in LN-229 cells and senescence induction in U-87 MG cells, promoted by prodrugs 1d and 1e, under hypoxic conditions. These results highlight the potential of these hypoxia-activated nitroaromatic-based triazene prodrugs for selective delivery of the cytotoxic methyldiazonium ion and support further optimization to provide a safer alternative for glioblastoma treatment.

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% (CC) 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.

Despite the success of endocrine therapies in treating ER-positive breast cancer, the development of resistance remains a significant challenge. Estrogen receptor targeting proteolysis-targeting chimeras (ER PROTACs) offer a unique approach by harnessing the ubiquitin-proteasome system to degrade ER, potentially bypassing resistance mechanisms. In this review, we present the drug design, efficacy and early clinical trials of these ER PROTACs. This review underscores the academic and industrial opportunities presented by this emerging technology, as well as the challenges that must be addressed to translate these findings into effective clinical therapies.

Nitrofuran and pyrazolopyrimidine-based compounds possess a broad antimicrobial spectrum including Gram-positive and Gram-negative bacteria. In the present work, a series of conjugates of these scaffolds was synthesized and evaluated for antimicrobial activity against and methicillin-resistant (MRSA). Many compounds showed MIC values of ≤2 μg ml, with compound 35 demonstrating excellent activity (MICs: 0.7 and 0.15 μg ml against and MRSA, respectively) and safety up to 50 μg ml in HepG2 cells. Compound 35 also exhibited no hemolytic activity, biofilm eradication, and effectiveness against efflux-pump-overexpressing strains (NorA, TetK, MsrA) without resistance development. It showed synergistic effects with vancomycin () and rifampicin (MRSA). Mechanistic studies revealed that compound 35 exhibits good membrane-targeting abilities, as evidenced by DAPI/PI staining and scanning electron microscopy (SEM). In an intracellular model, it reduced bacterial load efficiently in both and MRSA strains. With a strong profile, compound 35 demonstrated favorable oral pharmacokinetics at 30 mg kg and potent anti-MRSA activity, highlighting its potential against antibiotic-resistant infections.

A peptide segment that is 10 residues long at the C-terminal (CT) region of Cx43 is known to be involved in interactions, both with the Cx43 protein itself and with other proteins, that result in hemichannel (HC) activity regulation. Previously reported mimetic peptides based on this region (, , ) have been revealed to be promising therapeutic agents in the context of cardiovascular diseases. In this work, novel approaches, such as C- and N-terminal modification and cyclization, to improve the proteolytic stability and bioavailability of the peptide are presented. These efforts resulted in a set of unprecedented potent cyclic inhibitors of HC-mediated ATP release with a half-life largely exceeding 24 hours. Additionally, the introduction of a lipophilic moiety with different solubilizing linkers led to the generation of a novel series of water-soluble and lipidated peptides that exhibited high inhibitory capacity in assays at submicromolar concentrations. A cardiac endothelium targeting strategy was also adopted, exploiting the ability of the CRPPR peptide to selectively deliver the peptides to endothelial cells.

Some novel sulphonyl thiourea derivatives (7a-m) containing 4,6-diarylpyrimidine rings were designed and synthesized using a one-pot procedure. These compounds exhibited remarkable dual inhibitory activity against human carbonic anhydrase CA I, CA II, CA IX, and XII isoenzymes and some cancer cell lines. Among them, some thioureas had significantly more potent inhibitory activities in the order of 7l > 7c > 7f (against the CA I isoform), 7f > 7b > 7c (against the CA II isoform), 7c > 7g > 7a > 7b (against the CA IX isoform), and 7d > 7c > 7g > 7f (against the CA XII isoform). The obtained inhibitory activity data against the CA IX and XII isoforms showed that compound 7c was the most potent inhibitor in this sulphonyl thiourea series against enzyme CA IX, with = 125.1 ± 12.4 nM, while compound 7d was the most potent inhibitor against enzyme CA XII, with = 111.0 ± 12.3 nM. Compound 7c exhibited strong inhibitory activity among all four tested CA enzymes, while thiourea 7f was a potent inhibitor for enzymes CA I, II and XII. All these compounds demonstrated non-competitive inhibition of both enzymes. Some selected potential inhibitory compounds, including 7c, 7d, and 7g, exhibited remarkable cytotoxic activity against human cancer cell lines, including human breast adenocarcinoma (MCF-7), human liver adenocarcinoma (HepG2), human cervical epithelial carcinoma (HeLa), and human lung adenocarcinoma cells (A549). These compounds exhibited low cytotoxicity in the WI-38 cell line. The compounds 7c and 7d were the most potent inhibitors against tumour-associated CA IX and CA XII isoenzymes. Furthermore, these compounds exhibited remarkable inhibition against some cancer cell lines, such as MCF-7, HepG2, HeLa, and A549. They were subjected to screening for molecular docking and molecular dynamics simulations. The results of and studies revealed that compounds 7c and 7d were the most promising derivatives in this series owing to their significant effects on the studied CA IX and CA XII isoenzymes, respectively. The results showed that the sulphonyl thiourea moiety was deeply accommodated in the active site and interacted with zinc ions in the receptors.

Considering the multifactorial and complex nature of Alzheimer's disease and the requirement of an optimum multifunctional anti-Alzheimer's agent, a series of triazole tethered coumarin-eugenol hybrid molecules was designed as potential multifunctional anti-Alzheimer's agents using donepezil and a template. The designed hybrid molecules were synthesized a click chemistry approach and preliminarily screened for cholinesterase and Aβ aggregation inhibition. Among them, AS15 emerged as a selective inhibitor of AChE (IC = 0.047 μM) over butyrylcholinesterase (BuChE: IC ≥ 10 μM) with desired Aβ aggregation inhibition (72.21% at 50 μM) properties. In addition, AS15 showed protective effects against DNA damage caused by hydroxyl radicals originating from HO. Molecular docking and simulation studies confirmed the favorable interactions of AChE and the Aβ monomer desired for their inhibition. AS15 exhibited an LD value of 300 mg kg and showed significant improvements in memory and learning behavior in scopolamine-induced cognition impairment mouse-based animal models (Y-maze test and Morris water maze test) for behavioral analysis. Overall outcomes suggest AS15 as a potential preclinical multifunctional candidate for the management of Alzheimer's disease, and it serves as a promising lead for further development of potent and safer multifunctional anti-Alzheimer's agents.

Estrogen receptor β (ERβ) is aberrantly expressed in castration-resistant prostate cancer (CRPC). Therefore, a diagnostic and therapeutic ERβ probe not only helps to reveal the complex role of ERβ in prostate cancer (PCa), but also promotes ERβ-targeted PCa therapy. Herein, we reported a novel ERβ-targeted near-infrared fluorescent probe D3 with both imaging and therapeutic functions, which had the advantages of high ERβ selectivity, good optical performance, and strong anti-interference ability. In addition, it displayed excellent antiproliferative activity in CRPC cells. Finally, D3 was also successfully applied to the imaging of ERβ in the prostate cancer mouse model. Thus, this ERβ-targeted near-infrared fluorescent probe can be used as a potential tool for the study of ERβ-targeted diagnostic and therapeutic PCa.

Alzheimer's disease (AD) is a complex, incurable neurological condition characterized by cognitive decline, cholinergic neuron reduction, and neuronal loss. Its exact pathology remains uncertain, but multiple treatment hypotheses have emerged. The current treatments, single or combined, alleviate only symptoms and struggle to manage AD due to its multifaceted pathology. The developmental drugs target pivotal disease factors involved in the envisaged hypotheses and include targets such as amyloid aggregation, hyperphosphorylated tau proteins, and receptors like cholinergic, adrenergic, Present-day research focuses on multi-target directed ligands (MTDLs), which inhibit multiple factors simultaneously, helping slow the disease's progression. This review attempts to collate the recent information related to proposed hypotheses for AD etiology. It systematically organizes the advances in various therapeutic options for AD, with a particular emphasis on clinical candidates. Also, it is expected to help medicinal chemists design novel AD treatments based on available information, which could be helpful to AD patients.

The N/OFQ-NOP receptor is a fascinating peptidergic system with the potential to be exploited for the development of analgesic drugs devoid of side effects associated with classical opioid signalling modulation. To date, up to four X-ray and cryo-EM structures of the NOP receptor in complex with the endogenous peptide agonist N/OFQ and three small molecule antagonists have been solved and released. Despite the available structural information, the details of selective small molecule agonist binding to the NOP receptor in the active state remain elusive. In this study, by leveraging the available structural information and using N/OFQ(1-13)-NH as a reference compound, we developed a computational protocol based on docking followed by short molecular dynamics (MD) simulations that can suggest small molecule agonist binding modes at the NOP receptor that are reproducible and stable over time in the solvated membrane-embedded receptor active state and in agreement with known structure-activity relationship (SAR) data.

Bacterial infections pose a threat to human and animal health, and the formation of biofilm exacerbates the microbial threat. New antimicrobial agents to address this challenge are much needed. In this study, several new amphoteric compounds derived from the natural product coumarin were designed and synthesized by mimicking the structure and function of antimicrobial peptides. Strong inhibitory effect of 8b was observed on 29213 and five isolated clinically positive strains, with an MIC value of 1-4 μg mL, accompanied by the potential advantages of rapid sterilization and no drug resistance. The activity of 8b was supported by good antibacterial and anti-inflammatory effects in a mouse wound infection model. More importantly, good immunomodulatory effects, inhibition of biofilm formation, and biofilm clearance were detected in the treatment using 8b, which makes it a potential candidate antibacterial for controlling infections forming biofilm.