Exploring dimethoxy naphthalenyl methoxyphenyl quinazolinyl amine as a PDE10A inhibitor: In-silico studies, synthesis and binding interactions with serum albumin

• Published in: Journal of molecular liquids 2024-10, Vol.412, p.125788, Article 125788
• Main Authors: Mishra, Akanksha, Pooja, Gond, Chandraprakash, Singh, Vijay Kumar, Tiwari, Anjani K.
• Format: Article
• Language: English
• Subjects: ADMET; CD spectroscopy; Fluorescence spectroscopy; HSA; Molecular docking; Phosphodiesterase 10A; UV–visible spectroscopy
• ISSN: 0167-7322
• DOI: 10.1016/j.molliq.2024.125788

[Display omitted] •Design and synthesis of Dimethoxy naphthalenyl methoxyphenyl quinazolinyl amine (QPhN) as a potential PDE10A inhibitor.•Exploration of binding interaction of QPhN with HSA, emphasizing the role of Tryptophan residue.•Computational analysis of 28 alkoxy quinazoline derivatives leading to the discovery of QPhN as a promising PDE10A inhibitor.•ADME analysis supporting drug likeness and bioavailability of QPhN for CNS applications.•Application of QPhN in optical imaging, showcasing its potential for Trp measurements in HSA. Phosphodiesterase 10A (PDE10A) inhibitors stand out as key players in the quest for effective treatments against neurological disorders. Among them, Papaverine has gained attention for its ability to activate striatal output, hinting at potential antipsychotic properties. A thorough computational analysis of 28 alkoxy quinazoline derivatives derived from Papaverine led to the discovery of Dimethoxynaphthalenyl methoxyphenyl quinazolinyl amine (QPhN), addressing its exceptional docking score (-27.71) and binding energy (−44 kJ/mol). The main contributors of this binding were Gln716 and Phe719. Absorption, Distribution, Metabolism, Excretion (ADME) and Toxicity analysis predicted its drug likeness, bioavailability and highest CNS scoring (0.0409). Notably, its synthesis involved two-step process, first cyclic addition of dimethoxy quinazolinyl chloride and dioxaborolanyl phenol took place along with alkylation with bromomethyl naphthalene. To better understand the ADME profile of QPhN, its interaction with serum albumin (SA) was analyzed with the help of Photo physical studies. Fluorescence emission of SA was quenched to reveal the subtle shifts (distinct red shift of around 20 nm) in the protein’s microenvironment. Through static quenching analysis, a binding constant value in the range (K = 104 M−1) underscored the prevalence of non-covalent interactions between QPhN and SA with involvement of one binding site. Additionally, the interaction between QPhN and SA was enthalpically and entropically compelled to sub domain IIA with ΔH (−72.2 kJ/mol), ΔS (−210.37 J mol−1 K−1) and ΔG (−9.62 kJ/mol) values. The binding represents weak perturbation (1–3 %) of α-helix content of SA with increasing concentration of QPhN. The study highlighted the importance of QPhN as a promising marker for PDE10A.