CDK-1 and PARP-1 play crucial roles in breast cancer progression. Compounds acting as CDK-1 and/or PARP-1 inhibitors can induct cell death in breast cancer with a selective synthetic lethality mechanism. A mixed treatment by means of CDK-1 and PARP-1 inhibitors resulted in radical breast cancer cell growth reduction. Inhibitors with a dual target mechanism of action could arrest cancer progression by simultaneously blocking the DNA repair mechanism and cell cycle, resulting in advantageous monotherapy. To this aim, in the present work, we identified compound 645656 with a significant affinity for both CDK-1 and PARP-1 by a mixed ligand- and structure-based virtual screening protocol. The Biotarget Predictor Tool was used at first in a Multitarget mode to filter the large National Cancer Institute (NCI) database. Then, hierarchical docking studies were performed to further screen the compounds and evaluate the ligands binding mode, whose putative dual-target mechanism of action was investigated through the correlation between the antiproliferative activity data and the target proteins’ (CDK-1 and PARP-1) expression pattern. Finally, a Molecular Dynamics Simulation confirmed the high stability of the most effective selected compound 645656 in complex with both PARP-1 and CDK-1.

Molecular hybridization, which consists of the combination of two or more pharmacophores into a single molecule, is an innovative approach in drug design to afford new chemical entities with enhanced biological activity. In the present study, this strategy was pursued to develop a new series of 6,7-dimethoxy-4-piperazinylquinoline-3-carbonitrile derivatives (5a–k) with potential antibiotic activity by combining the quinoline, the piperazinyl, and the benzoylamino moieties, three recurrent frameworks in antimicrobial research. Initial in silico evaluations were conducted on the designed compounds, highlighting favorable ADMET and drug-likeness properties, which were synthesized through a multistep strategy, isolated, and fully characterized. The whole set was tested in vitro against Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 10145 representative Gram-positive and Gram-negative strains, respectively. Notably, 5k exhibited potent and selective activity against S. aureus (MIC 10 μM), with a dose- and time-dependent response and capability to affect cell membrane integrity. On the other hand, no significant activity was observed against P. aeruginosa. Further in silico docking and molecular dynamics studies highlighted strong interactions of 5k with bacterial enzymes, such as tyrosyl-tRNA synthetase, pyruvate kinase, and DNA gyrase B, suggesting potential modes of action. These findings underscore the value of the hybridization approach in producing new antimicrobial agents, guiding future optimization for broader-spectrum activity.

Aurones, particular polyphenolic compounds belonging to the class of minor flavonoids and overlooked for a long time, have gained significative attention in medicinal chemistry in recent years. Indeed, considering their unique and outstanding biological properties, they stand out as an intriguing reservoir of new potential lead compounds in the drug discovery context. Nevertheless, several physicochemical, pharmacokinetic, and pharmacodynamic (P3) issues hinder their progression in more advanced phases of the drug discovery pipeline, making lead optimization campaigns necessary. In this context, scaffold hopping has proven to be a valuable approach in the optimization of natural products. This review provides a comprehensive and updated picture of the scaffold-hopping approaches directed at the optimization of natural and synthetic aurones. In the literature analysis, a particular focus is given to nitrogen and sulfur analogues. For each class presented, general synthetic procedures are summarized, highlighting the key advantages and potential issues. Furthermore, the biological activities of the most representative scaffold-hopped compounds are presented, emphasizing the improvements achieved and the potential for further optimization compared to the aurone class.

The viral main protease is one of the most attractive targets among all key enzymes involved in the life cycle of SARS-CoV-2. Considering its mechanism of action, both the catalytic and dimerization regions could represent crucial sites for modulating its activity. Dual-binding the SARS-CoV-2 main protease inhibitors could arrest the replication process of the virus by simultaneously preventing dimerization and proteolytic activity. To this aim, in the present work, we identified two series’ of small molecules with a significant affinity for SARS-CoV-2 M^PRO, by a hybrid virtual screening protocol, combining ligand- and structure-based approaches with multivariate statistical analysis. The Biotarget Predictor Tool was used to filter a large in-house structural database and select a set of benzo[b]thiophene and benzo[b]furan derivatives. ADME properties were investigated, and induced fit docking studies were performed to confirm the DRUDIT prediction. Principal component analysis and docking protocol at the SARS-CoV-2 M^PRO dimerization site enable the identification of compounds 1b,c,i,l and 2i,l as promising drug molecules, showing favorable dual binding site affinity on SARS-CoV-2 M^PRO.

In the search for new anticancer compounds, quinoline and piperazine moieties represent the most promising pharmacophoric fragments for the development of more effective drugs. A particularly interesting approach in medicinal chemistry is molecular hybridization, where different known components are integrated into a single chemical entity, resulting in hybrid molecules with enhanced biological activity. In this study, we have developed a new series of 4‐(4‐benzoylpiperazin‐1‐yl)‐6‐nitroquinoline‐3‐carbonitrile compounds ( 8 a – l ), with potential anticancer effect, by combining the quinoline, the piperazinyl and the benzoylamino moieties. The rationalized compounds ( 8 a – l ) were first evaluated in silico to assess the ADMET and drug‐likeness profiles, synthesized using appropriate synthetic strategies and then tested in vitro under the National Cancer Institute DTP‐NCI60 program. The entire series exhibited potent anticancer activity against the renal cell carcinoma (RCC) cell line UO‐31, with compounds 8 c and 8 g effectively inhibiting cancer cell growth without excessive cytotoxic effects (growth percentages of −7 and −19, respectively). In silico induced fit docking (IFD) and molecular dynamics (MD) studies provided further insights into the putative mechanisms of action for both compounds, which were predicted to strongly bind key oncogenic proteins involved in RCC progression. The promising in vitro and in silico results herein presented provide a solid foundation for the development of a new series of small heterocyclic molecules with anticancer activity.

Breast cancer remains one of the most prevalent and lethal malignancies in women, particularly the estrogen receptor-positive (ER+) subtype, which accounts for approximately 70% of cases. Traditional endocrine therapies, including aromatase inhibitors, selective estrogen receptor degraders/antagonists (SERDs), and selective estrogen receptor modulators (SERMs), have improved outcomes for metastatic ER+ breast cancer. However, resistance to these agents presents a significant challenge. This study explores a novel therapeutic strategy involving the simultaneous inhibition of the estrogen receptor (ER) and the chaperone protein Hsp90, which is crucial for the stabilization of various oncoproteins, including ER itself. We employed a hybrid, hierarchical in silico virtual screening approach to identify new dual ER/Hsp90 inhibitors, utilizing the Biotarget Predictor Tool (BPT) for efficient multitarget screening of a large compound library. Subsequent structure-based studies, including molecular docking analyses, were conducted to further evaluate the interaction of the top candidates with both ER and Hsp90. Supporting this, molecular dynamics simulations demonstrate the high stability of the multitarget inhibitor 755435 in complex with ER and Hsp90. Our findings suggest that several small molecules, particularly compound 755435, exhibit promising potential as dual inhibitors, representing a new avenue to overcome resistance in ER+ breast cancer.