B-019

Cancer remains to be the second leading cause of death, since the available drugs and therapies may get failure due to the early-stage drug resistance, metastasis, poor pharmacokinetics, and toxic effects. This gap can be fulfilled by designing potential anticancer agent with the Phthalimide as a prime scaffold. The robust and reliable pharmacophore model was used for the designing of newer Phthalimide derivatives. Additionally, we clubbed 1,3,4-Oxadiazole with Phthalimide to fulfil these features. The predicted IC₅₀ for all the designed compounds are in µM range and DFT study also confirmed the reactive nature of these molecules. The designed compounds were synthesized and characterized by FT-IR, ¹H NMR, ¹³C NMR and Mass spectroscopy. The in-vitro anticancer evaluation was carried out by performing MTT assay on MCF-7 and HCT-116 cancer cell lines. All compounds showed moderate to potent anticancer activity. The compound B19 was found to be the most potent against both the MCF-7 and HCT-116 with IC₅₀ of 3.468 and 4.508 µM respectively. All the compounds showed good docking score in terms of binding affinity, lib dock score, CDOCKER interaction and binding free energy. MD Simulation study reviled good stability, compactness and rigidity of potent compound throughout the 100 ns run. ADMET results supports the good pharmacokinetics and lower toxicity. In conclusion, we suggest the compound B19 is potential drug-like candidate can be utilized in anticancer treatment on further confirmations. This study is widely useful for the medicinal chemists and scientific community.

Psoriasis is a chronic inflammatory disease that affects the quality of life of patients. The aromatic hydrocarbon receptor (AHR) plays a pivotal role in maintaining the skin barrier integrity. In this study, we conducted a comprehensive analysis of the structure-activity relationship of Tapinarof analogues. Among them, B19 showed low cytotoxicity (>40 μM) and potent AHR agonist activity with an EC₅₀ value of 2.01 nM, which was 14-fold stronger than that of Tapinarof (28.93 nM). B19 exhibited the ability to elevate the transcript levels of key AHR downstream pathway target genes, including CYP1A1 and CYP1B1. Upon topical application, B19 significantly ameliorated imiquimod (IMQ)-induced psoriasis-like cutaneous manifestations and repaired the barrier function of skin, concurrently downregulating the expression levels of CD206, CD36, IL-18, and MCP-1. These findings suggested that B19 represents a potential alternative to Tapinarof for the topical psoriasis treatment.