Novel benzenesulfonamide‐thiouracil conjugates with a flexible N‐ethyl acetamide linker as selective CA IX and CA XII inhibitors

Abstract

Novel benzenesulfonamide derivatives linked to diverse functionalized thiouracils through a flexible N-ethyl acetamide linker were designed and synthesized as carbonic anhydrase (CA) inhibitors. The synthesized candidates demonstrated a potent inhibitory activity against four different CA isoforms in the nanomolar range.Compound 10d showed more than twofold higher potency than the reference AAZ against CA II with K i of 5.65 and 12 nM, respectively. Moreover, compounds 10d and 20 revealed potent activity against CA IX with K i of 18.1 and 14.2 nM, respectively.In addition, 10c, 10d, 11b, 11c, and 20 demonstrated high potency against the CA XII isozyme with a K i range of 4.18-4.8 nM. Most of the synthesized derivatives displayed preferential selectivity toward the CA IX and CA XII isoforms over CA I and CA II. Compounds 11a and 20 exhibited favorable selectivity toward CA IX over CA II with a selectivity index (SI) of 14.36 and 16.62, respectively, and toward CA XII over CA II with SI of 71.01 and 51.19, respectively. Molecular docking simulations showed that the synthesized conjugates adopted comparable binding modes in the CA I, CA II, CA IX, and CA XII isoforms, involving the deep fitting of the sulfonamide moiety in the base of the CA active site via chelation of the Zn 2+ ion and H-bond interaction with the key amino acids Thr199 and/or Thr200. Moreover, the N-ethyl acetamide flexible linker enables the substituted thiouracils and fused thiouracil tail to achieve multiple interactions with the surrounding hydrophobic and hydrophilic regions.

Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021–Present)

“…Quinazoline is an aromatic heterocyclic scaffold consisting of fused pyrimidine and a benzene ring. The quinazoline motif is considered to be one of the most important heterocyclic ring systems in pharmaceutical chemistry, present in many compounds and endowed with tremendous biological activities [ 9 , 10 , 11 , 12 ]. The quinazoline nucleus and its derivatives were reported to have significant potential as promising enzyme inhibitors ( Figure 1 ).…”