Chondroitin sulfate proteoglycans (CSPGs) are extracellular matrix components that contain two structural parts with distinct functions: a protein core and glycosaminoglycan (GAG) side chains. CSPGs are known to be involved in important cell processes like cell adhesion and growth, receptor binding, or cell migration. It is recognized that the presence of CSPGs is critical in neuronal growth mechanisms including axon guidance following injury of nervous system components such as spinal cord and brain. CSPGs are upregulated in the central nervous system after injury and participate in the inhibition of axon regeneration mainly through their GAG side chains. Recently, it was shown that some CSPGs members like aggrecan, versican, and neurocan were strongly involved in brain disorders like bipolar disorder (BD), schizophrenia, and ADHD. In this paper, we present the chemical structure-biological functions relationship of CSPGs, both in health state and in genetic disorders, addressing methods represented by genome-wide and crystallographic data as well as molecular modeling and quantitative structure-activity relationship.

Malignant melanoma poses a significant global health burden. It is the most aggressive and lethal form of skin cancer, attributed to various risk factors such as UV radiation exposure, genetic modifications, chemical carcinogens, immunosuppression, and fair complexion. Photodynamic therapy is a promising minimally invasive treatment that uses light to activate a photosensitizer, resulting in the formation of reactive oxygen species, which ultimately promote cell death. When selecting photosensitizers for melanoma photodynamic therapy, the presence of melanin should be considered. Melanin absorbs visible radiation similar to most photosensitizers and has antioxidant properties, which undermines the reactive species generated in photodynamic therapy processes. These characteristics have led to further research for new photosensitizing platforms to ensure better treatment results. The development of photosensitizers has advanced with the use of nanotechnology, which plays a crucial role in enhancing solubility, optical absorption, and tumour targeting. This paper reviews the current approaches (that use the synergistic effect of different photosensitizers, nanocarriers, chemotherapeutic agents) in the photodynamic therapy of melanoma.

Diabetes represents a major health problem, involving a severe imbalance of blood sugar levels, which can disturb the nerves, eyes, kidneys, and other organs. Diabes management involves several synthetic drugs focused on improving insulin sensitivity, increasing insulin production, and decreasing blood glucose levels, but with unclear molecular mechanisms and severe side effects. Natural chemicals extracted from several plants such as Gymnema sylvestre, Momordica charantia or Ophiopogon planiscapus Niger have aroused great interest for their anti-diabetes activity, but also their hypolipidemic and anti-obesity activity. Here, we focused on the anti-diabetic activity of a few natural and synthetic compounds, in correlation with their pharmacokinetic/pharmacodynamic profiles, especially with their blood-brain barrier (BBB) permeability. We reviewed studies that used bioinformatics methods such as predicted BBB, molecular docking, molecular dynamics and quantitative structure-activity relationship (QSAR) to elucidate the proper action mechanisms of antidiabetic compounds. Currently, it is evident that BBB damage plays a significant role in diabetes disorders, but the molecular mechanisms are not clear. Here, we presented the efficacy of natural (gymnemic acids, quercetin, resveratrol) and synthetic (TAK-242, propofol, or APX3330) compounds in reducing diabetes symptoms and improving BBB dysfunctions. Bioinformatics tools can be helpful in the quest for chemical compounds with effective anti-diabetic activity that can enhance the druggability of molecular targets and provide a deeper understanding of diabetes mechanisms.

In this paper, we aimed to exploit and combine in the same molecule the carbazole and the 1,3,4-oxadiazole pharmacophores, to obtain novel carprofen derivatives, by using two synthesis pathways. For the first route, the following steps have been followed: (i) (RS)-2-(6-chloro-9H-carbazol-2-yl)propanonic acid (carprofen) treatment with methanol, yielding methyl (RS)-2-(6-chloro-9H-carbazol-2-yl)propanoate; (ii) the resulted methylic ester was converted to (RS)-2-(6-chloro-9H-carbazol-2-yl)propane hydrazide (carprofen hydrazide) by treatment with hydrazine hydrate; (iii) reaction of the hydrazide derivative with acyl chlorides led to N-[(2RS)-2-(6-chloro-9H-carbazol-2-yl)propanoil]-N′-R-substituted-benzoylhydrazine formation, which; (iv) in reaction with phosphorus oxychloride gave the (RS)-1-(6-chloro-9H-carbazol-2-yl)-1-(1,3,4-oxadiazol-2-yl)ethane derivatives. In the second synthesis pathway, new 1,3,4-oxadiazole ring compounds were obtained starting from carprofen which was reacted with isoniazid, in the presence of phosphorus oxychloride to form (RS)-1-(6-chloro-9H-carbazol-2-yl)-1-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]ethane. The synthesized compounds were characterized by IR, ¹H-NMR and ¹³C-NMR, screened for their drug-like properties and evaluated for in vitro cytotoxicity and antimicrobial activity. The obtained compounds exhibited a good antimicrobial activity, some of the compounds being particularly active on E. coli, while others on C. albicans. The most significant result is represented by their exceptional anti-biofilm activity, particularly against the P. aeruginosa biofilm. The cytotoxicity assay revealed that at concentrations lower than 100 μg/mL, the tested compounds do not induce cytotoxicity and do not alter the mammalian cell cycle. The new synthesized compounds show good drug-like properties. The ADME-Tox profiles indicate a good oral absorption and average permeability through the blood brain barrier. However, further research is needed to reduce the predicted mutagenic potential and the hepatotoxicity.

Within medicinal chemistry nowadays, the so-called pharmaco-dynamics seeks for qualitative (for understanding) and quantitative (for predicting) mechanisms/models by which given chemical structure or series of congeners actively act on biological sites either by focused interaction/therapy or by diffuse/hazardous influence. To this aim, the present review exposes three of the fertile directions in approaching the biological activity by chemical structural causes: the special computing trace of the algebraic structure-activity relationship (SPECTRAL-SAR) offering the full analytical counterpart for multi-variate computational regression, the minimal topological difference (MTD) as the revived precursor for comparative molecular field analyses (CoMFA) and comparative molecular similarity indices analysis (CoMSIA); all of these methods and algorithms were presented, discussed and exemplified on relevant chemical medicinal systems as proton pump inhibitors belonging to the 4-indolyl,2-guanidinothiazole class of derivatives blocking the acid secretion from parietal cells in the stomach, the 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine congeners’ (HEPT ligands) antiviral activity against Human Immunodeficiency Virus of first type (HIV-1) and new pharmacophores in treating severe genetic disorders (like depression and psychosis), respectively, all involving 3D pharmacophore interactions.

In a drug-repurposing-driven approach for speeding up the development of novel antimicrobial agents, this paper presents for the first time in the scientific literature the synthesis, physico-chemical characterization, in silico analysis, antimicrobial activity against bacterial and fungal strains in planktonic and biofilm growth state, as well as the in vitro cytotoxicity of some new 6,11-dihydrodibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)oximes. The structures of intermediary and final substances (compounds 7a–j) were confirmed by ¹H-NMR, ¹³C-NMR and IR spectra, as well as by elemental analysis. The in silico bioinformatic and cheminformatic studies evidenced an optimal pharmacokinetic profile for the synthesized compounds 7a–j, characterized by an average lipophilic character predicting good cell membrane permeability and intestinal absorption; low maximum tolerated dose for humans; potassium channels encoded by the hERG I and II genes as potential targets and no carcinogenic effects. The obtained compounds exhibited a higher antimicrobial activity against the planktonic Gram-positive Staphylococcus aureus and Bacillus subtilis strains and the Candida albicans fungal strain. The obtained compounds also inhibited the ability of S. aureus, B. subtilis, Escherichia coli and C. albicans strains to colonize the inert substratum, accounting for their possible use as antibiofilm agents. All the active compounds exhibited low or acceptable cytotoxicity levels on the HCT8 cells, ensuring the potential use of these compounds for the development of new antimicrobial drugs with minimal side effects on the human cells and tissues.