Current Topics in Medicinal Chemistry - Online First

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. M1 macrophages exhibit dual roles in the tumor microenvironment (TME), but the specific mechanisms underlying their involvement in HCC remain unclear.

M1-polarized macrophages were differentiated from THP-1 monocytes employing Phorbol 12-Myristate 13-Acetate (PMA) and lipopolysaccharide (LPS). Then, macrophage activity was determined based on Mean Fluorescence Intensity (MFI), and their metabolic capacity was assessed according to extracellular acidification rate (ECAR) and Oxygen Consumption Rate (OCR). Quantitative Real-Time PCR (qRT-PCR) was performed to assess the expression of polarization-related genes.

The results showed that LPS at a concentration higher than 10 ng/mL significantly affected the viability of macrophages differentiated from THP-1 monocytes but promoted the MFI of CD86. At the same time, LPS treatment notably enhanced the M1 polarization of macrophages, as evidenced by the upregulated expression of markers related to the M1 phenotype. Moreover, the mitochondrial oxidative metabolism of M1 macrophages shifted toward aerobic glycolysis under LPS treatment. When T-cells and HCC cells were co-cultured with M1 macrophages, the reactivity of T cells was enhanced, and the level of Bax (an apoptosis-enhancer) was increased. At the same time, the expression of Bcl-2 (an apoptosis-suppressor) was suppressed.

LPS-induced M1 macrophages exert antitumor effects through metabolic reprogramming and immune modulation, though further mechanistic studies are needed.

M1 macrophages inhibit HCC progression by activating T cells and inducing tumor cell apoptosis, offering novel insights for HCC immunotherapy.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are one of the most widely prescribed medications in the world, yet their applications as anti-inflammatory, analgesic, and anti-pyretic drugs remain principally restricted by their detrimental effects on the gastrointestinal tract (GIT) systems. The prodrug approaches have substantially combated the drawbacks of currently available marketed NSAIDs and also showed increased activity.

In the present study, an extensive literature review on mutual prodrugs of NSAIDs with natural antioxidants has been presented.

Different databases like ScienceDirect, Elsevier, PubMed, Google Scholar, etc. were used for an extensive search of articles related to NSAIDs, prodrug concepts, as well as research based on all of the NSAIDs-prodrug molecules prepared to date.

Recent developments in prodrug design have been explored that utilize naturally occurring antioxidants, including Thymol, Guaiacol, Menthol, Eugenol, Sesamol, Vanillin, and Umbelliferon, for the synthesis of mutual prodrugs by esterification methods. Many studies have shown that these prodrugs have significant stability in acidic pH while hydrolyzing in neutral and alkaline pH environments. This indicates their potential as advantageous therapeutic agents with enhanced safety profiles.

The mutual prodrug strategy offers a chance in medicinal chemistry to enhance the therapeutic and clinical efficiency of a drug that has certain unfavorable qualities that limit its clinical utility. This review enlightens mutual prodrugs of NSAIDs and antioxidants that are less harmful and beneficial to mankind, respectively.

This study aims to discover and design β-5 tubulin-specific covalent inhibitors for non-small cell lung cancer (NSCLC) that can minimize hematotoxicity, a major side effect of current microtubule-targeting agents (MTAs).

Current microtubule-targeting drugs cause toxicities such as hematotoxicity and multidrug resistance (MDR). The colchicine binding site in β-5 has Cys-239, whereas β-1 has Ser-239, allowing selective inhibition based on the reactivity differences for covalent reactions.

β-5 and β-1 tubulin models were developed, and covalent docking and virtual screening were conducted to identify selective inhibitors targeting the β-5 tubulin colchicine binding site. Twenty hits were selected, and a comparative study was carried out between β-5 and β-1 to evaluate the selectivity and binding potential of the inhibitors.

Among the 20 identified hits, four compounds demonstrated selective inhibition of β-5 tubulin, exhibiting stronger binding affinity for β-5 over β-1 tubulin. Molecular dynamics studies further confirmed their stability and enhanced binding, highlighting their potential as promising candidates for further drug development.

The study identified four novel β-5 tubulin-specific covalent inhibitors that may act as potential therapeutic agents for NSCLC, with the possibility of reduced hematotoxicity. These findings suggest that selective inhibition could help minimize side effects, addressing a critical need in cancer treatment.

Nanomedicine is a rapidly growing field in pharmaceutical science, driven by the enhanced quality of nano-formulations that improve the treatment of various diseases. Nano-sized novel drug delivery techniques for herbal pharmaceuticals have the potential to enhance activity and address concerns related to medicinal plants in the future. Natural chemicals show promise in various neurodegenerative diseases, but their permeability across the blood-brain barrier prevents them from reaching the nervous system. By improving molecular monitoring, synthesis, and diagnostics, pharmaceutical nanotechnology provides improved controlled drug delivery for the treatment of neurodegeneration.

The evaluated and investigated data from recent studies were gathered using Google Scholar as a search engine. We reviewed and analysed research publications from databases like Bentham Science, Elsevier, PubMed, and ScienceDirect, among others, to summarize the findings.

Curcumin, Centella asiatica, thymoquinone, Hypericum perforatum, Panax ginseng, quercetin, piperine, and a variety of other herbs and herbal medicines have all been examined for their potential to aid in the treatment of brain disorders like Alzheimer's disease. To enhance drug bioavailability in the brain, nanoformulations, including phytosomes, transferosomes, ethosomes, and niosomes, have been utilized as pharmaceuticals.

Herbs and herbal medicines have been synthesized into nanoparticle form to enhance tissue distribution, achieve sustained delivery, and protect against physicochemical degradation while also increasing the solubility and bioavailability of poorly soluble herbal products. To overcome physiological complications, researchers must develop lab-scale approaches, characterization methodologies, and targeting tactics for nanoformulations with high translational potential early in product development.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by the impaired utilization of glucose, insulin resistance, or reduced insulin production. Although conventional pharmacologic agents like metformin, sulfonylureas, and thiazolidinediones are effective in regulating elevated blood glucose levels, they are often associated with some adverse effects, such as weight gain and liver problems.

The present review summarizes the possibility of using phytochemicals as safer alternatives for the management of DM by modulation of molecular receptors.

Several studies have reported that certain antioxidant phytochemicals exhibit inhibitory effects on key signaling pathways involved in glucose metabolism and insulin sensitivity under in vitro conditions. Therefore, this review will focus on the therapeutic potential of phytochemicals in modulating molecular targets, such as PPARs, GPR119, free fatty acid (FFA) receptors, glucocorticoid receptors, and others. For this purpose, a systematic and extensive literature search was carried out to obtain relevant data, focusing on the prospect of phytochemicals in modulating molecular receptors for diabetes mellitus (DM) management. Electronic databases, including PubMed, Scopus, ScienceDirect, and Google Scholar, were accessed for articles up to March 2025.

Curcumin, resveratrol, and quercetin are bioactive molecules that increase the sensitivity of the body to insulin and protect the pancreatic β-cells from oxidative stress. Natural agents, such as garlic, green tea, and blackcurrants, possess an antidiabetic action by inhibiting enzymes, such as α-glucosidase, and increasing the uptake of glucose. The co-administration of synthetic drugs along with natural agents has a synergistic effect in improving glycemic control with fewer side effects. Examples include resveratrol with metformin or curcumin with thiazolidinediones.

The findings of this review should be validated at the clinical level in future research studies, including toxicity profiling and formulation optimization, to maximize the therapeutic potential of phytochemicals in the management of DM.

Cancer continues to be a significant public health issue and one of the leading causes of death globally. In this context, developing new, potent, and more specific treatments against this disease is urgent.

A total of 15 benzoxathiolone-thiazolidinones hybrids were synthesized in a 5-step route and tested for their cytotoxicity against five human cancer cell lines: AGP-01 (gastric), SKMEL-103 (melanoma), HCT-116 (colon), CAL27 (tongue), and K562 (leukemia), as well as a non-tumoral cell line MRC-5.

Compounds 3-(6-hydroxy-2-oxobenzo[d][1,3]oxathiol-5-yl)-2-(4-nitrophenyl)thiazolidin-4-one and 2-(2,4-dichlorophenyl)-3-(6-hydroxy-2-oxobenzo[d][1,3]oxathiol-5-yl)thiazolidin-4-one exhibited good activity against the K562 leukemia cell line, with IC50 values of 4.0 μM and 5.3 μM, respectively. Docking studies demonstrated that these compounds likely bind to the BCR-ABL1 kinase, a key protein in the pathogenesis of chronic myeloid leukemia (CML).

The study suggests these benzoxathiolone-thiazolidinone hybrids could be promising lead compounds for developing new anticancer agents targeting leukemia.

Although E. coli is considered a normal human microbiota, it may cause life-threatening infections such as septicemia, urinary tract infections, and enteric infections. Moreover, multidrug-resistant strains are a serious challenge in the clinic due to high mortality rates and the limited number of therapeutic options. Hence, the current study aimed to benefit from pink rose petals as a source of green synthesis of copper nanoparticles (Cu-NPs), to investigate the antibacterial features against multidrug-resistant E. coli, and to measure the cytotoxicity of Cu-NPs.

Pink rose petals were used as a reducing agent for Cu-NP synthesis, and then XRD, zeta potential, UV-Vis, FTIR, SEM, and DLS analyses were performed to characterize the synthesized NPs. Moreover, the MIC and zone of inhibition values of Cu-NPs were measured and compared to common antibiotics. Additionally, the MTT assay was performed to assess the cytotoxicity.

The green synthesized Cu-NPs were spherical and uniform with a size of ~200 nm. The MIC of Cu-NPs was 1024 μg/ml on the MDR strain of E. coli, representing the antibacterial activity comparable to levofloxacin (p-value>0.05) but less than imipenem and trimethoprim (p-value<0.001). Moreover, the CC50 of synthesized Cu-NPs was 731.2 μg/ml and significantly lower than the studied antibiotics (p-value<0.001).

The findings may suggest Cu-NPs as a promising antibacterial strategy against MDR strains of E. coli, however, further studies are encouraged to clarify the safety of optimized doses.