Electronic effect‐dependent intramolecular non‐covalent interactions on the activity of 4,4‐dimethylimidazolidin‐2‐one pharmacophore‐based androgen receptor antagonists

• Published in: Chemical biology & drug design Vol. 101; no. 3; pp. 614 - 625
• Main Authors: Yaragani, Muralikrishna, Yadlapalli, Prasad, Raghavan, Sriram, Giridhar, Thota, Mandava, Venkata Basaveswara Rao, Singh, Ravindra Vikram, Kottapalli, Rajasekhara Prasad, Chinnusamy, Saravanan
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.03.2023
• Subjects: 4,4‐dimethylimidazolidin‐2‐one; Androgen Antagonists - pharmacology; androgen receptor; Androgen Receptor Antagonists - pharmacology; Androgen Receptor Antagonists - therapeutic use; Androgens - metabolism; Androgens - pharmacology; Androgens - therapeutic use; Biochemistry & Molecular Biology; Cell Line, Tumor; Chemistry, Medicinal; Drug Resistance, Neoplasm; Humans; Life Sciences & Biomedicine; Male; Nitriles; non‐covalent interactions; Pharmacology & Pharmacy; Pharmacophore; prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Receptors, Androgen - metabolism; Science & Technology; thiohydantoin; thiohydantoin; DESIGN; PROTEIN; 4-dimethylimidazolidin-2-one; non-covalent interactions; prostate cancer; androgen receptor; AMPLIFICATION; 4; GENE; MUTATION; BIOLOGY; RESISTANT PROSTATE-CANCER; 4,4-dimethylimidazolidin-2-one
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.14151

Because androgen receptor (AR) signalling is important for the development and progression of prostate cancer (PC), AR antagonists are utilized in clinical practices to treat PC and are referred to as androgen deprivation therapy (ADT). However, continued administration of AR antagonists often results in the development of resistance, known as castration‐resistant prostate cancer (CRPC). Despite castration, it has been demonstrated that AR signalling continues to be fundamental to tumour growth. In this regard, a series of readily synthesizable 4,4‐dimethylimidazolidine‐2‐one pharmacophore‐based AR antagonists (FAR01‐FAR11) were designed and synthesized. Androgen‐dependent LNCaP PC cell line was used to test the AR‐antagonist activity of these compounds in vitro and compared with the U.S. Food and Drug Administration (FDA) approved second‐generation enzalutamide. In our previous work, rigid thiohydantoin pharmacophore in enzalutamide is replaced by the flexible 4,4‐dimethylimidazolidin‐2‐one. In order to improve the flexibility further, one methylene group is introduced between the pharmacophore and one of the aromatic ring. Despite the fact that the amide functional group is a crucial characteristic for building AR antagonists, this class of molecules lacks one. FAR06 has the exact same activity as enzalutamide (IC50: 0.782 μM) with an IC50 value of 0.801 μM among the series of compounds. We evaluated the activity of an amide group free series of compounds (FAR01‐FAR11) as an androgen receptor antagonist to that of a second‐generation enzalutamide approved by the US Food and Drug Administration (FDA). Among the compounds, FAR06 shows exactly same activity as enzalutamide. For the first time, we have observed a relation between electronic effect‐dependent non‐covalent interactions and the molecule's anti‐prostate cancer activity.