In recent years, non-tuberculous mycobacterial infections are definitely increasing worldwide. In particular, in Europe and North America, the non-tuberculous mycobacteria’s (NTM) incidence exceeds that of tuberculosis, with 1.0 to 1.8 case per 100,000 individuals. NTM are commonly found in the environment (soils, natural or urban water sources) and can be defined as opportunistic bacteria. Known for their pulmonary pathogenicity, several NTM can be particularly harmful to people with weakened immune system or pre-existing lung diseases such as cystic fibrosis, bronchiectasis or chronic obstructive pulmonary disease (COPD). The NTM classification is based on their type of growth: the slow-growing species include Mycobacterium avium complex (MAC), M. xenopi and M. kansasii, while M. abscessus and its MABSC complex and M. fortuitum belong to the rapid-growing species. Treatment options require a combination of three antibiotics including a macrolide, which depend on the strain. The treatment covers 18 to 24 months, with many associated side effects, and the cure rate remains moderate (e. g. 52 % to 60 % for MAC infections). Otherwise, mycobacterial resistance to macrolides, in particular MAC, represents a major challenge in treating infections. Our drug discovery strategy focuses on the development of a novel family of antibiotics based on a quinoline core, targeting NTM. Some developed or commercial antibiotics such as bedaquiline (BQ) or mefloquine (MQ) containing this scaffold have shown potent antimycobacterial activity. Thus, this work aims to design and synthesize innovative quinoline-based carboxamides, bearing an amide function on the position 4 of the quinoline ring. In addition, the determination of physico-chemical properties and the biological evaluation of synthesized compounds will be presented.

The mechanism of action of peptide inhibitors involves two steps. 3CLpro inhibitors, which mimic natural peptide substrates, initially bind to 3CLpro and form a non-covalent complex, while the attacking group (warhead) undergoes a nucleophilic attack, forming covalent bonds with the Cys145 residue. In this paper, we present a new small-molecule inhibitor of the main coronavirus protease, 3CLPro, based on the carbocyclically substituted peptidomimetic N-(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)-(2Z)-3-(thiophen-2-yl)prop-2-enamide (TEA-Leu-Pld-CHO).

This low-toxicity compound (CC50 was 187.5 μg/ml) exhibits antiviral activity against modern coronavirus strains, including SARS-CoV-2. This substance exhibits sufficient solubility in aqueous solutions due to the one-step conversion of the aldehyde group to sodium bisulfite as a prodrug. To study the antiviral properties of the TEA-Leu-Pld-CHO compound, the SARS-CoV-2 human coronavirus strain, passage 4, with an infectious activity of 106 TCID50/mL for Vero-E6 cells, was used.

An experiment to assess cell viability in the antiviral efficacy assay was conducted over a range of drug concentrations from 375.0 to 0.37 μg/mL, by titrating the initial concentration in the wells of a 96-well plate. The antiviral activity of the compounds was assessed visually under a microscope 96 hours after infection by inhibiting the viral CPE in a Vero E6 cell culture. The IC50 for TEA-Leu-Pld-CHO was 5.8 μg/mL. Thus, Si was 32.

The proposed compound, given its high antiviral activity and low cytotoxicity, as well as its economic and synthetic availability, can be recommended as a candidate for preclinical and clinical trials to develop an etiotropic antiviral drug aimed at inhibiting an important enzyme—the main protease of the coronavirus, including modern strains of SARS-CoV-2.

Hydrazones are compounds that exhibit a broad range of biological activities, including anticancer, antifungal, antimicrobial, anti-inflammatory, anticonvulsant properties. On the other hand, pyrene is a highly conjugated polycyclic aromatic hydrocarbon that has been used in antimicrobial and bioimaging studies, showing activity against wild-type bacteria and fungal species. In this work, we synthesized new hydrazones derived from 1-pyrenecarboxaldehyde (1) with various para-substituted phenylhydrazines (2a-d) bearing electron-withdrawing groups such as fluorine, chlorine, and bromine, since these halogens are associated with enhanced biological activity and improved permeability. Additionally, an electron-donating group (4-OCH₃) was included due to its prominence in several known derivatives with anticancer activity.

For the synthesis of hydrazones 3a-d, a mixture of 1-pyrenecarboxaldehyde (1) and p-phenylhydrazines (a: 4-Cl, b: 4-Br, c: 4-CF₃, d: 4-OCH₃) was stirred in ethanol at 80 °C, yielding the desired products (3a-d) in 73-90%, which were characterized by IR spectroscopy, ¹H and ¹³C NMR, mass spectrometry, and single-crystal X-ray diffraction of 3d, obtained by slow evaporation from ethanol. Hydrazones 3a-d exhibited bacteriostatic activity against Mycobacterium tuberculosis, and compound 3d was active with a MIC = 40 µg/mL. Moreover, all compounds showed anticancer activity against breast cancer cells (MCF-7) with and IC₅₀ value <6.25 µg/mL, and compound 3d (4-OCH₃) exhibits the highest inhibitory activity against cervical cancer cells (Hep-2) with an IC₅₀ of 67.2 µg/mL. Molecular docking studies were performed using the binding pocket of PDB: 2OZ5. The protein-ligand complex of compound 3d exhibited interactions with catalytic residues Met146, Arg230, and Met226.

Inflammation is a key pathological process underlying numerous acute and chronic disorders, and while non-steroidal anti-inflammatory drugs (NSAIDs) remain widely prescribed, their clinical utility is restricted due to adverse effects such as gastrointestinal bleeding, hepatotoxicity, and the emergence of resistance during prolonged therapy. To overcome these limitations, heterocyclic scaffolds have emerged as privileged structures in medicinal chemistry, with benzimidazole and oxadiazole derivatives showing strong potential as anti-inflammatory agents. In the present study, a series of benzofused nitrogen-containing heterocyclic derivatives were designed and synthesized by employing 2-mercaptobenzimidazole as the core pharmacophore. The synthetic pathway involved the initial formation of thioacetate from 2-mercaptobenzimidazole and ethyl-2-chloroacetate in ethanolic KOH, followed by hydrazinolysis to yield the corresponding acetohydrazide, which was subsequently cyclized with various substituted aromatic acids in the presence of H₂SO₄ to afford the final heterocyclic derivatives. Structural elucidation was achieved using FT-IR, ¹H-NMR, and mass spectrometry, where spectral data confirmed the disappearance of primary amine/amide peaks and the appearance of diagnostic C=N, C–O–C, and secondary amine signals. Proton NMR spectra revealed characteristic –CH₃/–CH₂ resonances (1.0–4.0 ppm) and aromatic signals (7.0–9.0 ppm), while molecular ion peaks (M+1) in mass spectra validated the expected molecular weights. Toxicological evaluation using AOT 425 guidelines established an LD₅₀ of 1103 mg/kg, suggesting an acceptable safety margin. Pharmacological screening via carrageenan-induced rat paw edema assay demonstrated that the synthesized compounds, administered at 110 and 130 mg/kg, produced significant inhibition of inflammation, comparable to standard reference drugs. Overall, the findings highlight the promising anti-inflammatory potential of the synthesized benzofused heterocycles and support further optimization for drug development

Acetylcholinesterase (AChE) plays a key role in the pathophysiology of Alzheimer’s disease (AD) by promoting excessive hydrolysis of acetylcholine, leading to a marked cholinergic deficit. This increased enzymatic activity is directly linked to cognitive decline in AD, making AChE inhibition a cornerstone of current symptomatic treatment strategies [1]. In this context, organocalcogen compounds, particularly selenium derivatives, have gained attention due to their redox, antioxidant, and enzyme-modulating properties, as well as their versatility in coordinating with biomolecules [2,3]. In this study, the synthesis of two distinct classes of SeCN-containing derivatives, alkyl and aryl, was performed. The alkyl derivatives were obtained via established procedures involving bimolecular nucleophilic substitution reactions. In contrast, the aryl derivatives were synthesized through aromatic nucleophilic substitution, initiated by diazonium salt formation. As a result, a series of five compounds was successfully prepared and subsequently subjected to AChE inhibition assays in vitro using samples of mouse brains. Biological activity was assessed through a colorimetric assay using acetylthiocholine as substrate. Analysis of Variance (ANOVA) revealed a significant difference among groups [F_(26,52) = 34.97; p<0.0001]. Aromatic derivatives showed inhibitory activity from 15 µM, while aliphatic analogues were active from 10 µM. Rivastigmine (200 µM, a clinical AChE inhibitor) was used as positive control. The results demonstrate that selenocyanates present relevant inhibitory activity against cerebral AChE in vitro and stand out as promising candidates for the development of novel therapeutic approaches for AD.

Interleukin-1β (IL-1β) is a prototypical cytokine of the IL-1 family that regulates innate and adaptive immunity. Its cognate receptor, interleukin-1 receptor type 1 (IL-1R1), is therefore a tractable target for anti-inflammatory drug discovery. The peptide antagonist AF10847 binds IL-1R1 and disrupts the IL-1β/IL-1R1 protein–protein interface, validating the receptor’s druggability. However, its peptidic nature entails poor oral bioavailability and unfavorable developability. This study aimed to discover non-peptidic small molecules capable of inhibiting IL-1R1 using a 3D shape-similarity strategy anchored on AF10847. The IL-1R1/AF10847 co-crystal structure was prepared for modeling, and the binding pocket was delineated using FPocket, DoGSiteScorer, and DeepSite. In silico alanine scanning of the complex identified interaction “hot spots” at the protein-protein interface. Following comprehensive conformer enumeration of AF10847, a ROCS query capturing its molecular envelope and salient pharmacophoric features was constructed and deployed to virtually screen large purchasable libraries (Enamine, ChemDiv, Asinex and NCI Open Database). Candidates were ranked by Tanimoto similarity score and lightly filtered for drug-likeness prior to structure-based triage. Top-ranked molecules underwent ensemble molecular docking into multiple IL-1R1 conformations to accommodate receptor flexibility, with poses assessed by consensus scoring and interaction-fingerprint analysis for consistency with the AF10847 recognition pattern. Short all-atom molecular-dynamics simulations were then performed to evaluate pose stability via heavy-atom RMSD and hydrogen-bond occupancy and to obtain qualitative affinity estimates using trajectory-averaged metrics. This computational cascade identified several chemically diverse small-molecule candidates predicted to engage IL-1R1 in persistent, well-packed poses with favorable interaction networks. These in silico hits constitute tractable starting points for experimental validation, including biochemical binding assays and cellular readouts of IL-1β signaling, orthogonal selectivity counterscreens early ADMET profiling to guide medicinal-chemistry optimization toward orally available IL-1R1 modulators.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the sixth leading cause of death worldwide, with cases continuing to rise at an alarming rate and imposing major social, economic, and healthcare burdens. Despite over a century of research, effective disease-modifying therapies remain elusive. Several pathogenic mechanisms—including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, acetylcholine deficiency, and oxidative stress—have been explored to elucidate AD progression. Among these, targeting the Aβ cascade has emerged as a particularly promising therapeutic strategy, especially in the early stages of the disease. Consequently, the development of small molecules capable of modulating amyloid aggregation represents a critical avenue for advancing novel AD treatments.

In this work, a novel library of N-benzylphenoselenazine (PSZ) derivatives (8a–j) was designed, synthesized, and systematically evaluated for their ability to inhibit Aβ40 aggregation, a central hallmark of AD pathology. Structure–activity relationship (SAR) studies using thioflavin T fluorescence assays demonstrated significant inhibition across the series, ranging from 26.0% to 86.4%. Compounds 8i and 8j exhibited particularly strong effects, reducing aggregation by ~75% and 86% at 25 μM, respectively—comparable to standard reference inhibitors resveratrol (~85%) and methylene blue (~96%). Transmission electron microscopy (TEM) confirmed their ability to disrupt Aβ40 fibril formation, while computational docking studies indicated favorable interactions with the hydrophobic KLVFFA motif of the Aβ40 dimer, stabilizing its structure and impeding further aggregation.

These findings establish N-benzylphenoselenazines as promising lead candidates for therapeutic development aimed at the amyloid cascade. By combining synthetic design, biological evaluation, and computational modeling, this study underscores the potential of selenium-based scaffolds as innovative agents for addressing the unmet therapeutic challenges of Alzheimer’s disease.

Abstract:

The highly dynamic microtubules of the mitotic spindle are well-established biochemical targets for anticancer drugs such as paclitaxel, vinblastine, and vincristine. However, a significant clinical challenge is the emergence of resistance to these agents, highlighting the urgent need for novel anticancer compounds that target tubulin. In this study, a panel of chloroquinoline derivatives was synthesized and characterized using ¹H NMR, FTIR, and mass spectrometry. The antiproliferative activity of these compounds was evaluated against the breast cancer cell lines MCF-7 and MDA-MB-231. Of the tested molecules, CQ-9 and CQ-14 displayed IC₅₀ values of 5.6 μM and 4.55 μM, respectively, against MDA-MB-231 cells, while CQ-9 exhibited an IC₅₀ of 13.05 μM for MCF-7 cells. All compounds (CQ-1 to CQ-14) were subjected to molecular docking studies using the Schrödinger software suite to investigate their interactions with tubulin. The resulting ligand-protein complexes were analyzed for binding energies, and the most stable complexes were selected for further molecular dynamics simulations. Tubulin was chosen as a likely target owing to the structural similarity of the reported compounds to quinolinyl and other herteroaryl chalcones that have shown to inhibit Tubulin by binding to Colchicine binding site. Hence , we used specific crystal structure of tubulin (PDB id: 1SA0) co-complexed with Colchicine for our molecular docking studies.

Malaria remains a major global public health challenge, particularly in sub-Saharan Africa. According to the World Health Organization, an estimated 263 million cases of malaria and approximately 597,000 deaths were reported in 2023. The disease is caused by Plasmodium parasites, transmitted through the bites of female Anopheles mosquitoes. Among the five species infecting humans, P. falciparum remains both the most prevalent in Africa and the most lethal. Over the past century, P. falciparum has progressively developed resistance to artemisinin-based combination therapies (ACT), the current front-line treatment recommended by the WHO.

This resistance correlates with mutations in the pfk13 gene, associated with artemisinin resistance, as well as alterations in Pf multidrug resistance 1 (PfMDR1), a transporter which regulates the influx of nutrients and molecules, including arylaminoalcohols, into the parasite’s digestive vacuole. These changes weaken the efficacy of ACT, ultimately reducing the overall effectiveness of the treatment and highlighting the urgent need to discover new effective antimalarial agents.

Herein, we report the design and synthesis of enantiopure aminopyridine derivatives built on the enpiroline scaffold as promising antimalarial compounds. Their optimized synthesis route and key physicochemical properties will be outlined, followed by an evaluation of their in vitro biological activity. Most of the compounds display potent in vitro inhibition close to the nanomolar range against both 3D7 and W2 P. falciparum strains. Cytotoxicity assays showed excellent selectivity indices, mostly above 500. A structure-activity relationship analysis will also be presented, offering valuable insights for further optimization.

A series of derivatives based on 3-vinyl-quinoxalin-2(1H)-one were designed, synthesized, and screened for their dual activity against amyloid beta (Aβ) aggregation and human acetylcholinesterase (hAChE). In this comprehensive study, sixteen compounds were meticulously evaluated using the Ellman assay, revealing that MHA-2 and MHA-15 emerged as the most effective inhibitors of hAChE, exhibiting low micromolar IC₅₀ values. These values highlight the compounds’ ability to inhibit the enzyme at remarkably low concentrations, suggesting high potency. To further investigate, the molecular docking and dynamics simulations were conducted. These computational approaches provided additional support for the experimental findings, revealing stable interactions with key catalytic and peripheral residues of hAChE enzyme. Furthermore, PAMPA-BBB (Parallel Artificial Membrane Permeability Assay for the Blood-Brain Barrier) analysis confirmed their favourable blood–brain barrier permeability, while competitive displacement of propidium iodide indicated strong binding at the peripheral anionic site (PAS) of hAChE. Moreover, the Thioflavin T fluorescence assays demonstrated that both compounds effectively suppressed Aβ aggregation, inhibiting not only spontaneous self-assembly but also hAChE-induced fibrillization in a concentration-dependent manner. In conclusion, the compounds MHA-2 and MHA-15 emerge as promising lead scaffolds with dual functionality in hAChE inhibition and Aβ aggregation prevention, coupled with favourable BBB permeability, supporting their potential as therapeutic candidates for Alzheimer’s disease.