Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT₆ receptors appear to be a particularly attractive target from a therapeutic perspective, due to their involvement not only in cognitive processes, but also in depression and psychosis. In this work, we present the synthesis and broad biological characterization of a new series of 18 compounds with a unique 1,3,5-triazine backbone, as potent 5-HT₆ receptor ligands. The main aim of this research is to compare the biological activity of the newly synthesized sulfur derivatives with their oxygen analogues and their N-demethylated O- and S-metabolites obtained for the first time. Most of the new triazines displayed high affinity (K_i < 200 nM) and selectivity towards 5-HT₆R, with respect to 5-HT_2AR, 5-HT₇R, and D₂R, in the radioligand binding assays. For selected, active compounds crystallographic studies, functional bioassays, and ADME-Tox profile in vitro were performed. The exciting novelty is that the sulfur derivatives exhibit an agonistic mode of action contrary to all other compounds obtained to date in this chemical class herein and previously reported. Advanced computational studies indicated that this intriguing functional shift might be caused by presence of chalcogen bonds formed only by the sulfur atom. In addition, the N-demethylated derivatives have emerged highly potent antioxidants and, moreover, show a significant improvement in metabolic stability compared to the parent structures. The cholinesterase study present micromolar inhibitory AChE and BChE activity for both 5-HT₆ agonist 19 and potent antagonist 5. Finally, the behavioral experiments of compound 19 demonstrated its antidepressant-like properties and slight ability to improve cognitive deficits, without inducing memory impairments by itself. Described pharmacological properties of both compounds (5 and 19) allow to give a design clue for the development of multitarget compounds with 5-HT₆ (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives.

In this study, a search for new therapeutic agents that may improve the antibacterial activity of conventional antibiotics and help to successfully overcome methicillin-resistant Staphylococcus aureus (MRSA) infections has been conducted. The purpose of this work was to extend the scope of our preliminary studies and to evaluate the adjuvant potency of new derivatives in a set of S. aureus clinical isolates. The study confirmed the high efficacy of piperazine derivatives of 5-arylideneimidazol-4-one (7–9) tested previously, and it enabled the authors to identify even more efficient modulators of bacterial resistance among new analogs. The greatest capacity to enhance oxacillin activity was determined for 1-benzhydrylpiperazine 5-spirofluorenehydantoin derivative (13) which, at concentrations as low as 0.0625 mM, restores the effectiveness of β-lactam antibiotics against MRSA strains. In silico studies showed that the probable mechanism of action of 13 is related to the binding of the molecule with the allosteric site of PBP2a. Interestingly, thiazole derivatives tested were shown to act as both oxacillin and erythromycin conjugators in S. aureus isolates, suggesting a complex mode of action (i.e., influence on the Msr(A) efflux pump). This high enhancer activity indicates the high potential of imidazolones to become commercially available antibiotic adjuvants.

In view of the unsatisfactory treatment of cognitive disorders, in particular Alzheimer’s disease (AD), the aim of this review was to perform a computer-aided analysis of the state of the art that will help in the search for innovative polypharmacology-based therapeutic approaches to fight against AD. Apart from 20-year unrenewed cholinesterase- or NMDA-based AD therapy, the hope of effectively treating Alzheimer’s disease has been placed on serotonin 5-HT₆ receptor (5-HT₆R), due to its proven, both for agonists and antagonists, beneficial procognitive effects in animal models; however, research into this treatment has so far not been successfully translated to human patients. Recent lines of evidence strongly emphasize the role of kinases, in particular microtubule affinity-regulating kinase 4 (MARK4), Rho-associated coiled-coil-containing protein kinase I/II (ROCKI/II) and cyclin-dependent kinase 5 (CDK5) in the etiology of AD, pointing to the therapeutic potential of their inhibitors not only against the symptoms, but also the causes of this disease. Thus, finding a drug that acts simultaneously on both 5-HT₆R and one of those kinases will provide a potential breakthrough in AD treatment. The pharmacophore- and docking-based comprehensive literature analysis performed herein serves to answer the question of whether the design of these kind of dual agents is possible, and the conclusions turned out to be highly promising.

Several studies confirmed the reciprocal interactions between adrenergic and serotoninergic systems and the influence of these phenomena on the pathogenesis of anxiety. Hence, searching for chemical agents with a multifunctional pharmacodynamic profile may bring highly effective therapy for CNS disorders. This study presents a deep structural insight into the hydantoin-arylpiperazine group and their serotonin/α-adrenergic activity. The newly synthesized compounds were tested in the radioligand binding assay and the intrinsic activity was evaluated for the selected derivatives. The computer-aided SAR analysis enabled us to answer questions about the influence of particular structural fragments on selective vs. multifunctional activity. As a result of the performed investigations, there were two leading structures: (a) compound 12 with multifunctional adrenergic-serotonin activity, which is a promising candidate to be an effective anxiolytic agent; (b) compound 14 with high α_1A/α_1D affinity and selectivity towards α_1B, which is recommended due to the elimination of probable cardiotoxic effect. The structural conclusions of this work provide significant support for future lead optimization in order to achieve the desired pharmacodynamic profile in searching for new CNS-modulating agents.

Due to complex etiology, a promising approach to find an effective therapy of Alzheimer's disease (AD) lies in the search for multitarget ligands. Within this study, we have identified novel 1,3,5-triazine derivatives that modulate either the serotonin 5-HT₆ receptor and the fatty acid amide hydrolase (FAAH) enzyme, also slightly inhibiting acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) enzymes, thus representing pioneering multitarget approach to address key pathological mechanisms in AD. Among the synthesized compounds, the m-chlorobenzyl- 7 (5-HT₆R pK_i = 7.59) and the trimethoxybenzyl- 23 (5-HT₆R pK_i = 6.33) derivatives exhibited the most favorable multitarget action, with 5-HT₆R selectivity over other GPCR off-targets. Comprehensive molecular modeling provided insights into the compounds interactions with the molecular targets considered. In vitro evaluations revealed satisfactory metabolic stability and low risks of toxicity, including neurotoxicity. Notably, 23 demonstrated significant neuroprotective effects against Aβ_1-42-induced toxicity in hippocampal model (HT-22). Furthermore, in a Novel Object Recognition (NOR) test, both 7 and 23 ameliorated MK-801-induced memory deficits in rats. The results indicate the therapeutic potential for these first-in-class dual modulators of both, endocannabinoid system and serotonergic neurotransmission, to address neurodegenerative diseases such as AD.

The clinical failure of selective serotonin 5-HT₆ receptor (5-HT₆R) antagonists in Alzheimer's disease (AD) highlights the need for multitarget therapeutic strategies addressing the multifactorial nature of neurodegeneration. Building upon our pioneering discovery of the first-in-class dual 5-HT₆R/FAAH (fatty acid amide hydrolase) modulators among O-ether triazine compounds, we here report a comprehensive lead-optimization campaign centered on the triazine-based compound MR3b, identified as a promising lead in the search for AD treatment. Structural modifications based on scaffold contraction and chalcogen bioisosterism generated a focused library of 1,3,5-triazine derivatives with diversified GPCR and FAAH profiles. Several compounds displayed nanomolar affinities for 5-HT₆R, 5-HT_2AR, and D₂R, alongside improved FAAH inhibition and antioxidant properties. Sulfur and selenium substitutions markedly enhanced receptor affinity and reduced cytotoxicity compared to the oxygen-containing lead. Selected compounds demonstrated significant neuroprotective effects in cellular models of AD-related pathology, including mitochondrial dysfunction, amyloid-β, and glutamate-induced toxicity. Furthermore, the thio-analogue 4c effectively reversed memory deficits in vivo, showing superior CNS penetration (Kp,brain = 0.78), an expanded therapeutic window (NOR test), and improved safety relative to MR3b. This study identified compound 4c as a second-generation lead and underscores the potential of multitarget triazine-based ligands combining serotonergic modulation and FAAH inhibition as potential disease-modifying candidates for AD and related neurodegenerative disorders.