“Novichok” refers to a new group of nerve agents called the A-series agents. Their existence came to light in 2018 after incidents in the UK and again in 2020 in Russia. They are unique organophosphorus-based compounds developed during the Cold War in a program called Foliant in the USSR. This review is based on original chemical entities from Mirzayanov's memoirs published in 2008. Due to classified research, a considerable debate arose about their structures, and hence, various structural moieties were speculated. For this reason, the scientific literature is highly incomplete and, in some cases, contradictory. This review critically assesses the information published to date on this class of compounds. The scope of this work is to summarize all the available and relevant information, including the physicochemical properties, chemical synthesis, mechanism of action, toxicity, pharmacokinetics, and medical countermeasures used to date. The environmental stability of A-series agents, the lack of environmentally safe decontamination, their high toxicity, and the scarcity of information on post-contamination treatment pose a challenge for managing possible incidents.

Tuberculosis (TB) imposes a major global health challenge, aggravated by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains. Scaffold hopping, a medicinal chemistry approach that modifies the molecular backbone of known bioactive compounds, has emerged as a promising tool in the development of novel drugs, including TB therapeutics. This perspective provides an insight into the application of scaffold hopping across varying degrees of structural modifications, highlighting successful case studies targeting key Mtb pathways, including energy metabolism, cell wall synthesis, proteasome function, and respiratory processes. Beyond traditional and in silico methods, scaffold hopping has spurred the discovery of compounds with improved pharmacological profiles, such as improved pharmacokinetics, enhanced efficacy, reduced toxicity, and resistance circumvention. The findings support scaffold hopping’s potential to address the limitations of current anti-TB drugs as a versatile and innovative approach to accelerate TB drug discovery.

Alzheimer’s disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood–brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.

Alzheimer’s disease (AD) is a complex disease with an unknown etiology. Available treatments, limited to cholinesterase inhibitors and N-methyl-d-aspartate receptor (NMDAR) antagonists, provide symptomatic relief only. As single-target therapies have not proven effective, rational specific-targeted combination into a single molecule represents a more promising approach for treating AD, and is expected to yield greater benefits in alleviating symptoms and slowing disease progression. In the present study, we designed, synthesized, and biologically evaluated 24 novel N-methylpropargylamino-quinazoline derivatives. Initially, compounds were thoroughly inspected by in silico techniques determining their oral and CNS availabilities. We tested, in vitro, the compounds’ effects on cholinesterases and monoamine oxidase A/B (MAO-A/B), as well as their impacts on NMDAR antagonism, dehydrogenase activity, and glutathione levels. In addition, we inspected selected compounds for their cytotoxicity on undifferentiated and differentiated neuroblastoma SH-SY5Y cells. We collectively highlighted II-6h as the best candidate endowed with a selective MAO-B inhibition profile, NMDAR antagonism, an acceptable cytotoxicity profile, and the potential to permeate through BBB. The structure-guided drug design strategy applied in this study imposed a novel concept for rational drug discovery and enhances our understanding on the development of novel therapeutic agents for treating AD.

Persistent chemical warfare agents (CWAs), designed for deposition as liquid droplets or coarse aerosols, pose prolonged environmental and forensic risks due to their persistence on contaminated surfaces. Roofing materials represent large, exposed areas in urban environments and may act as important reservoirs of CWAs following a release. However, their role in controlling contaminant fate and forensic detectability remains poorly understood. In this study, the behavior of four persistent CWAs - A-230, A-234 (Novichoks), cyclosarin (GF), and sulfur mustard (HD) - was investigated on five representative roofing materials differing in composition. Extraction efficiency, long-term persistence, and the divergence between matrix-retained and surface-accessible contamination were systematically evaluated using comparative bulk extraction and wipe sampling approaches. Dissipation half-lives, degradation-product formation, and long-term forensic detectability were assessed using gas chromatography-mass spectrometry. Results showed strong matrix-dependent behavior. A-series agents exhibited the highest persistence, particularly in porous cement-based materials. Wipe sampling consistently recovered only a fraction of the deposited mass and declined faster than bulk extraction, indicating rapid migration of agents into the matrix interior. Transformation products remained detectable in all materials after 90 days, even when parent compounds were substantially depleted. These findings demonstrate that roofing materials represent significant but often neglected reservoirs controlling the long-term retention, transformation, and forensic detectability of persistent CWAs. The results highlight the need to extend current decontamination and risk-assessment paradigms to include such surfaces and emphasize the importance of matrix-adapted sampling and analytical strategies in urban contamination scenarios.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health challenge, especially with the rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Current treatment regimens are prolonged and associated with significant toxicity, underscoring the need for novel therapeutic agents. This study investigates a new series of 2,4-disubstituted 5-(aryl-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidine derivatives as potential antitubercular agents. The most promising compound, 74, exhibited potent anti-TB activity, including against MDR strains, with a MIC₉₉ of 2 µM. Structure-activity relationship studies identified critical substitutions at positions 2- and 4- of the core scaffold that enhanced antimycobacterial potency, while bulkier aromatic moieties at position 5- were preferred. Despite its high efficacy, 74 demonstrated significant cytotoxicity, inhibition of cytochrome P450 enzymes and cardiotoxicity through hERG channel inhibition, highlighting challenges in further development. Pharmacokinetic studies of 74 revealed favorable systemic exposure with a prolonged half-life, suggesting its potential for less frequent dosing. Nonetheless, in vitro assays demonstrated rapid metabolic turnover, likely due to high intrinsic clearance, and the compound's elevated logD values further indicate the need for structural modifications to improve both solubility and metabolic stability. Efforts to introduce more polar substituents at the 4-position led to a loss of anti-TB activity, emphasizing the complexity of balancing potency and safety.