Current Medicinal Chemistry - Volume 32, Issue 41, 2025

Infection remains a significant global health concern, with millions of new cases and deaths occurring due to infectious diseases. Currently, chemoprophylaxis and chemotherapy are the primary treatments, but side effects and toxicities pose challenges. Pathogenic microorganisms have developed resistance to antimicrobial medications. Nitrogen containing heterocyclic scaffolds possess the potential in drug discovery and are explored in various fields like pharmaceuticals, cosmetics, and agrochemicals. To minimize antimicrobial drug resistance, there is a need to design potent, safer antimicrobial lead compounds with higher selectivity and minimal cytotoxicity.

The present review aims to outline several recent developments in medicinal chemistry aspect of nitrogenous heterocyclic derivatives with the following purposes: (1) To cast light on the recent literature reports of the last eight years ranging from 2015 to 2023 describing anti-microbial potential of nitrogen-containing heterocyclic derivatives which includes pyrazole, pyrazoline, imidazole, tetrazole and quinoline; (2) To brief the recent developments in the medicinal chemistry of nitrogenous heterocyclic derivatives that is directed towards their anti-microbial profile; (3) To summarize the complete correlation of structural features of nitrogenous heterocyclic molecules with the pharmacological action including in silico as well as mechanistic studies to provide thoughts accompanying the generation of lead molecules.

Antimicrobial potential of nitrogenous heterocyclic molecules has been displayed by relating the structural features of various lead candidates with their in vitro as well as in vivo antimicrobial outcomes. In contrast, in silico computational analysis from different articles also helped to predict the SAR of potent molecules.

Nitrogen containing heterocycles are involved in a range of natural to synthetic analogues with keen antimicrobial potency. It is an emerging need to generate new nitrogenous heterocyclic molecules in order to tackle the drug resistance in micro-organisms with more targeted selectivity as well as specificity.

To limit the side effects associated with them and to combat the microbes acquired resistance towards the current drug regimen, novel nitrogenous heterocycle based antimicrobial agents are essential to be developed. This review connects the structural units present in lead compounds with their promising antimicrobial action.

The development of Methicillin-Resistant Staphylococcus aureus (MRSA) presents a significant risk to worldwide health and necessitates the creation of novel antimicrobial approaches. The enzyme dehydrosqualene synthase (CrtM), necessary for the bacterial species Staphylococcus aureus to produce staphyloxanthin, is a viable candidate for medicinal investigation. Blocking CrtM hampers the synthesis of staphyloxanthin, reducing the pathogen's ability to cause disease and making it more vulnerable to both the immune system and conventional antibiotics. This study aimed to target the CrtM protein using in-silico approaches and identified its inhibitors.

Tanimoto's similarity of 406,621 unique natural compounds collected from the COCONUT database was calculated using the known inhibitor of CrtM, hesperidin. Further, machine learning-based QSAR screening was performed on these natural compounds where two compounds showed promising binding with the CrtM protein (4299376 and 12897366). A binding score of -9.49 kcal/mol was found for 4299376 and 12897366, respectively, via molecular docking; this value was close to that of the control drug, hesperidin, which was -9.55 kcal/mol. Molecular dynamics simulations conducted at 30 ns and with complexes of MM/GBSA demonstrated binding free energies of -14.38 kcal/mol for 12897366 and -42.72 kcal/mol for 4299376, respectively. 4299376 was selected further for 200 ns MD simulation because of its high binding affinity and stability in the RMSD plots.

Additionally, post 200 ns MD analysis and MM/GBSA analysis showed the consistent stability and strong binding of 4299376 with CrtM (RMSD = 0.3 nm and binding free energy of -37.30 kcal/mol). Moreover, the critical residue Gln165 of CrtM was found to have a hydrogen bond with 4299376 in the 0 ns, 100 ns, and 200 ns conformation. Overall, 4299376 performed well in the PCA, free energy landscape, and per-residue decomposition, proving it is an effective CrtM binder. The free energy perturbation (FEP) analysis revealed that as the system progressed from fully bound (λ = 0) to decoupled (λ = 10), the free energy (∆G) changed from 6.56 kT to -4.38 kT, signifying a reduction in binding free energy and implying an increase in entropy and solvation effects that stabilize the ligand in the decoupled state. This underscores the entropic contribution and solvent interactions as critical determinants in the lowering of binding free energy.

This study concluded that 4299376 exhibits considerable therapeutic potential and could be investigated further for its potential use as an inhibitor against CrtM of S. aureus.

The purpose of this scoping review is to provide researchers with a comprehensive knowledge map and identify existing knowledge gaps.

Glaucoma is the leading cause of irreversible blindness worldwide. ROCK inhibitors are a novel class of intraocular pressure-lowering drugs that specifically target trabecular meshwork cells. Current research on ROCK inhibitors is dispersed across multiple directions, and their precise mechanisms of action in glaucoma treatment remain incompletely understood. For these reasons, we sought to integrate the existing evidence using a scoping review approach.

Relevant articles published between 2014 and 2024 were identified and screened using keywords in the PubMed and Embase databases. Articles were analyzed based on the inclusion and exclusion criteria.

The collected studies were categorized into three main themes: intraocular pressure reduction, neuroprotection, and anti-fibrosis. A total of 23 articles were included in the review. We found that studies related to intraocular pressure reduction accounted for the majority (approximately 74%), while research on neuroprotection and anti-fibrosis was relatively limited (approximately 14% each). Furthermore, among the 23 included articles, only one was a systematic review or meta-analysis.

ROCK inhibitors directly act on the trabecular meshwork to lower IOP and have potential neuroprotective and anti-fibrotic effects. However, these potential effects require further clinical trials to validate their efficacy in humans. In the future, more systematic reviews and meta-analyses are also needed to integrate and summarize the current primary research findings.

LGALS3BP exhibits differential expression in various types of tumors. This study aimed to analyze its potential diagnostic and prognostic value in Triple-negative Breast Cancer (TNBC).

We conducted a comprehensive analysis of LGALS3BP's differential expression and its association with patient survival outcomes using data from public databases. To further validate these findings, Immunohistochemistry (IHC) experiments were performed to confirm the differential expression of LGALS3BP protein in TNBC. Additionally, we also investigated the relationship among LGALS3BP, tumor immune infiltration, and drug sensitivity.

Results indicated LGALS3BP to be significantly upregulated in TNBC, with its high expression correlating with improved survival outcomes. Furthermore, LGALS3BP expression correlated with immune cell infiltration. Notably, high LGALS3BP expression may confer a greater likelihood of benefiting from immunotherapy.

LGALS3BP may serve as a diagnostic and prognostic biomarker for TNBC.

Sarcopenia, an aseptic chronic inflammatory disease, is a complex and debilitating disease characterized by the progressive degeneration of skeletal muscle. PANoptosis, a novel proinflammatory programmed cell death pathway, has been linked to various diseases. However, the precise role of PANoptosis-related features in sarcopenia remains uncertain.

According to the intersection of differentially expressed genes (DEGs) in the sarcopenia dataset GSE167186 and the PANoptosis gene set, we classified patients into PANoptosis-related subtypes (PANRS) using consensus clustering. The DEGs of PANRS were intersected with weighted gene co-expression network analysis (WGCNA). Protein-protein interaction network and cytoHubba algorithms were employed to further identify potential genes related to PANoptosis. The most characteristic genes were selected using LASSO regression and validated by ROC curve analysis, followed by relevant immune infiltration analysis. Additionally, small-molecule drug screening was performed using Cmap. The relative expression levels of hub genes in sarcopenia were confirmed by PCR. Finally, single-cell analysis and GSEA were used to examine the distribution and function of hub genes.

Thirty-five candidate genes were identified through WGCNA and PANRS. Machine learning and ROC curve analysis revealed three core genes: LTBP2, ETS2, and H3.3B, all of which were up-regulated in patients with sarcopenia (p<0.01). Immune infiltration analysis indicated that these three diagnostic genes were linked to the activation of NK cells and macrophages. Single-cell analysis demonstrated that LTBP2 was mainly localized in fibroblasts, while ETS2 and H3.3B exhibited a uniform distribution. Enrichment analysis indicated that the three hub genes were predominantly associated with the inhibition of energy metabolism.

In this study, the hub genes LTBP2, ETS2, and H3.3B associated with PANoptosis in sarcopenia were successfully identified through a combination of bioinformatics and experimental verification methods. This establishes a foundation for new candidate diagnostic and therapeutic targets for sarcopenia.

Parkinson's disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic cells and as of now, there is no established definitive treatment available for this condition.

In this study, the focus was on investigating the impact of SVAK-12, a small molecule that can cross the blood-brain barrier and remain stable without structural changes. The effect of SVAK-12 was investigated in vitro on neurotoxicity, in vivo model of Parkinson's diseases and in silico.

Through in vitro and in vivo experiments, as well as molecular docking simulations, it was found that SVAK-12 (375 ng.ml) led to increased cell viability, reduced cellular damage, and decreased production of NO and ROS. Additionally, it boosted levels of important neurotrophic factors like BDNF (130.49%) and GDNF (116.38%), potentially aiding in alleviating motor disability and depression. The study also highlighted SVAK-12's potential as a therapeutic candidate for neurological disorders due to its ability to increase tyrosine hydroxylase expression and dopamine levels (4.84 times). While it did not significantly improve motor symptoms in vivo, it did enhance motor asymmetry in the forelimbs and gene expression related to brain regions. Besides, it induced significant BMP-2 gene expression in substantial nigra regions without significant changes in GDNF and Nurr1 gene expression in the striatum expression. The docking of SVAK-12, Levodopa, Amantadine, Biperiden, Selegiline, and Rasagiline to the binding site of GFRα1, sortilin, and TrkB showed that SVAK-12 had greater MolDock score than Selegiline and Amantadine for GFRα1 and greater than amantadine for Sortilin and TrKB.

Overall, the study suggests that SVAK-12's neuro-biocompatibility, ability to reduce free radicals, and enhanced neurotrophic factors make it a promising candidate as a neuroprotective drug.