Synthesis, In Silico and In Vitro Studies of Potential Glucosamine‐6‐phosphate Synthase and Lanosterol‐14α‐demethylase Inhibitors

Abstract

AbstractSome derivatives of phenothiazine and phenoxazine compounds were synthesized via Hiyama‐cross coupling reaction protocol. The intermediates were prepared by reacting 2‐aminothiophenol, 2‐aminopyridin‐3‐ol and 4,5‐diamino‐6‐hydroxylpyrimidin‐2‐thiol with 2,3‐dibromonaphthalene‐1,4‐dione in alkaline medium of anhydrous sodium carbonate. These intermediates were subjected to the fluoride‐free Hiyama cross‐coupling reaction with 2‐(dimethylsilyl)pyridine and dimethyl(2‐thienyl)silanol using magnetically separable Pd/Fe3O4 as the catalyst under aqueous conditions to yield the derivatives. Molecular descriptors of these compounds were evaluated for their drug‐likeness. Pharmacokinetic parameters were also evaluated. Molecular docking studies were performed. The synthesized compounds showed drug‐likeness. Pharmacokinetic evaluation reveals a strong plasma protein binding and potentials to cross blood‐brain barrier. 6‐(Thiophen‐2‐yl)‐5H‐11‐azabenzo[a]phenoxazin‐5‐one (8 b) and 11‐Amino‐9‐thio‐6‐(thiophen‐2‐yl)‐5H‐8,11‐diazabenzo[a]phenoxazin‐5‐one (9 b) showed highest binding energies of −5.74 and −7.25 kcal/mol with the protein targets glucosamine‐6‐phosphate synthase (2VF5) and lanosterol‐14α‐demethylase (3JUV) respectively.