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Histone deacetylases (HDAC) are well‐established epigenetic targets for cancer therapy, with several HDAC inhibitors already approved for clinical use. Despite their potential, the clinical application of HDAC inhibitors, particularly HDAC1‐selective compounds, faces significant challenges. These include poor pharmacokinetics, limited bioavailability, and a lack of selectivity, which often necessitates to combine these inhibitors with other drugs for improved efficacy. Their limitations as standalone therapies emphasize the urgent need for further research and development. In this study, the dataset of 71 compounds were used to generate various pharmacophore models, among them DDRRR_1 was generated as the best pharmacophore model with a survival score of 6.148. The 3D‐QSAR data of theses compound showed a significant result with the values of R2 = 0.95 and Q2 = 0.87 in the atom‐based model and R2 = 0.901 and Q2 = 0.77 in the field‐based model. R‐group enumeration study generated novel 6426 compounds which was further screened through virtual screening study. The top‐scoring compound was M1 with the highest docking score (−8.804 kcal/mol) where hydroxy amide is important for interaction with HDAC1 protein. The ADME analysis demonstrated the compound's drug‐like characteristics. Overall, all hit compounds showed pharmacokinetic characteristics found within the range that is considered safe for human usage. This study findings have the potential to be applied further in the development of HDAC1 inhibitors for the treatment of gastric cancer. [ABSTRACT FROM AUTHOR]

A pentadentate diamide ligand, N,N′‐di(pyridine‐2‐yl)pyridine‐2,6‐dicarboxamide (L1H2) and its tetranuclear Cu(II) complex [Cu4(L1)2(μ3‐OH)2(H2O)3(ClO4)](ClO4) ⋅ H2O are reported. X‐ray crystal structure of the complex reveals that it has an open‐book type architecture. Two central copper atoms are connected to each other by two hydroxo bridges. Each of these two hydroxo bridges also connects the two central copper atoms to one of the two terminal copper atoms. Variable temperature susceptibility measurements show that χMT decreases with the temperature, indicating a strong antiferromagnetic behavior. With the help of DFT calculations the magnetic data was analyzed using the spin Hamiltonian H=−2 J1S3 ⋅ S4 −2 J2(S3 ⋅ S1+ S3 ⋅ S2+ S4 ⋅ S1+ S4 ⋅ S2)−2 J3S1 ⋅ S2 (where subscripts 1 and 2 refer to the terminal copper atoms and 3 and 4 refer to the central copper atoms). The best fit was obtained with 2 J1=−322 cm−1, 2 J2=+34.8 cm−1, 2 J3=−8.8 cm−1 and g=2.18, indicating a δ‐type interaction between terminal copper atoms. The complex proves to be an avid binder of ct‐DNA, with apparent binding constant (Kapp) value estimated as 1.536×107 M−1. In vitro experiments indicate that the Cu(II) complex reduced the proliferation of HCT116 cells among other cell lines. This reduction of cell proliferation may be attributed to the enhancement of intracellular ROS, along with modulation and disruption of cell cycle associated proteins. SKC conceptualized the project, arranged funding and involved in overall coordination among collaborators, analyzing the data, and writing the paper. AM was involved in doing the experimental work on synthesis of the compounds, carrying out analytical and spectroscopic measurements, collecting X‐ray crystallographic data and DNA binding experiments. MS, SM and KDS were involved in study of anticancer activities of the complex. SS helped in refining X‐ray structure of the complex. MC did the magnetic measurements and analysis whereas AF did the DFT calculations. [ABSTRACT FROM AUTHOR]