Current Topics in Medicinal Chemistry - Volume 25, Issue 11, 2025

Several chemical studies described the physiological efficacy of 1,4-dihydropyridines (DHPs). DHPs bind to specific sites on the α1 subunit of L-type calcium channels, where they demonstrate a more pronounced inhibition of Ca²⁺ influx in vascular smooth muscle compared to myocardial tissue. This selective inhibition is the basis for their preferential vasodilatory action on peripheral and coronary arteries, a characteristic that underlies their therapeutic utility in managing hypertension and angina. Among the vascular-selective DHPs, nifedipine, felodipine, and isradipine are key representatives, with nifedipine often considered the archetype due to its widespread use and efficacy in promoting vascular relaxation. Significant efforts have been made to modify the structure of nifedipine, the prototype of DHPs to better understand structure-activity relationships (SARs) and amplify calcium-modulating effects.

The objective of this study is to explore the SARs of various DHPs and the implications of 1,4-dihydropyrimidines (DHPMs) to block L- (CaV1.2)/T-type (CaV3.1 and CaV3.2) calcium channels subtypes in medicinal chemistry and physiology as calcium channel blockers (CCBs).

We have searched public databases such as National Library of Medicine (NLM), PubMed, and Google Scholar. Collected information pertinent to these chemical entities from reviews, and original articles. We have used keywords to search in these databases such as ‘calcium channel physiology’, ‘calcium channel blockers’, ‘medicinal chemistry’, ‘1,4-dihydropyridines’, and ‘1,4-dihydropyrimidines’, ‘structure-activity relationship’. We included the original articles, short communications, meta-analysis, and review articles published from the years 1975 to 2024.

Previous efforts by medicinal chemists have made significant strides in the synthesis of DHPs and DHPMs. These researchers have focused on creating CCBs that could effectively replicate the pharmacological properties of those currently in clinical use. While the standard one-pot synthesis of DHPMs typically involves three key components under various reaction conditions, more intricate synthetic routes have also been explored. These include enzyme-catalyzed processes, solvent-free reactions, ultrasonic methods, conventional reactions, acid-catalyzed pathways, and microwave-assisted synthesis, each of which offers distinct advantages and potential for the efficient production of DHPMs. DHPs have been the focus of significant research efforts to improve their potency and selectivity. However, a major limitation identified for this class of compounds is their short plasma half-life, potentially caused by metabolic oxidation to pyridine derivatives. To address these limitations, developing DHPMs through efficient modifications of the DHP scaffold has been explored. This research has also investigated the quantitative structure-activity relationships (QSARs) of C2-substituted DHPMs, fused 1,4-dihydropyrimidines, N3-substituted DHPMs, the bioactive role of fused pyrimidines, and comparison with fourth-generation CCBs, drug combinations considering their impact on calcium channel physiology. Subsequently, we discussed the efficacy of various CCBs, which are in clinical trials, lifestyle modifications, and other emerging technologies to ameliorate cardiovascular diseases.

Ongoing research into DHPs and DHPMs has greatly advanced our understanding of their SARs and potential as CCBs. Diverse synthetic methods, including enzyme-catalyzed, solvent-free, and microwave-assisted techniques, have been developed, enhancing the production and pharmacological properties of DHPMs. Future research should aim to optimize the DHP and DHPM scaffolds to improve potency, selectivity, and metabolic stability. Focus on significant modifications, such as C2 and N3 substitutions, could lead to more selective and potent CCBs. Additionally, integrating QSAR models and high-throughput screening will help identify promising clinical candidates, potentially expanding DHPMs' therapeutic use beyond cardiovascular diseases. In summary, continued exploration of novel DHPMs and innovative synthesis approaches will be key to developing next-generation calcium channel blockers with improved efficacy and safety.

Scedosporium apiospermum is a multidrug-resistant filamentous fungus that causes localized and disseminated diseases. Our group has previously described that metal-based complexes containing copper(II) or silver(I) ions complexed with 1,10-phenanthroline-5,6-dione (phendione) inhibited the viability of S. apiospermum conidial cells.

The effects of these promising complexes, [Cu(phendione)3](ClO4)2.4H2O (Cu-phendione) and [Ag(phendione)2]ClO4 (Ag-phendione), on vital biological processes, production of key virulence attributes and interaction events of S. apiospermum were investigated using a comprehensive multimodal approach.

The results demonstrated that both Cu-phendione and Ag-phendione effectively inhibited the viability of S. apiospermum mycelial cells in a dose-dependent manner. Furthermore, these test complexes, at varying concentrations, inhibited the transition of S. apiospermum conidia into hyphae. Scanning electron microscopy revealed significant structural alterations in the fungal cells, including changes to surface sculpturing and overall morphological architecture, following treatment with the complexes. A marked reduction in the expression of key surface molecules, such as mannose/glucose-rich glycoconjugates, fibronectin-binding proteins, and the well-known adhesin peptidorhamnomannan further supported these ultrastructural changes. The treatment also impaired adhesive interactions, reducing the fungus's ability to form biofilms on polystyrene surfaces and diminishing its interaction with macrophages, lung epithelial cells, and fibroblasts. Notably, treatment of infected macrophages with the complexes led to a significant reduction in the number of intracellular fungal cells.

The results provide information about the effects of silver- and copper-phendione complexes on cellular and virulence aspects of the emerging fungus S. apiospermum.

Piperidines are among the essential synthetic fragments for designing drugs and play a significant role in the pharmaceutical industry. The synthesis of newer derivatives by incorporating different amines paves the way for the introduction of novel drug combinations for current cancer treatments.

The new combinations of 1-(4-bromo-2-(pyrrolidine-1-yl) benzyl) piperidine derivatives were synthesized by adding various amino groups. All the synthesized derivatives were characterized using NMR and LC-MS. The anti-cancer activity of all the synthesized derivatives was studied on three different cell lines, A549 (lung cancer), HCT-116 (colon cancer), and MCF-7(breast cancer), using an MTT assay. The most potent compounds, 7h and 7k were further evaluated for cell cycle and tubulin polymerization inhibitory activity. Further, in-silico analysis for the same properties was performed using molecular docking using MM/GBSA and validated by RMSD.

All the synthesized derivatives showed selective cytotoxic potential against different cancer cell lines. Most of the derivatives displayed comparable anticancer potential in comparison to 5-FU. The most potent derivative, 7h, further arrests the cancer cells in the G2/M phase and prevents tubulin polymerization. The same was further confirmed using molecular docking on the colchicine binding site.

The derivative that arrests the cancer cells in the G2/M phase of the cell cycle and induces depolymerization can be developed as a good lead for further development.