Uracil as a Zn-Binding Bioisostere of the Allergic Benzenesulfonamide in the Design of Quinoline–Uracil Hybrids as Anticancer Carbonic Anhydrase Inhibitors

Abstract

A series of quinoline–uracil hybrids (10a–l) has been rationalized and synthesized. The inhibitory activity against hCA isoforms I, II, IX, and XII was explored. Compounds 10a–l demonstrated powerful inhibitory activity against all tested hCA isoforms. Compound 10h displayed the best selectivity profile with good activity. Compound 10d displayed the best activity profile with minimal selectivity. Compound 10l emerged as the best congener considering both activity (IC50 = 140 and 190 nM for hCA IX and hCA XII, respectively) and selectivity (S.I. = 13.20 and 9.75 for II/IX, and II/XII, respectively). The most active hybrids were assayed for antiproliferative and pro-apoptotic activities against MCF-7 and A549. In silico studies, molecular docking, physicochemical parameters, and ADMET analysis were performed to explain the acquired CA inhibitory action of all hybrids. A study of the structure–activity relationship revealed that bulky substituents at uracil N-1 were unfavored for activity while substituted quinoline and thiouracil were effective for selectivity.

Design and synthesis of new spirooxindole candidates and their selenium nanoparticles as potential dual Topo I/II inhibitors, DNA intercalators, and apoptotic inducers

“…The spirooxindoles were synthesised by refluxing isatin with two equivalents of 6-aminouracil derivatives 44 , 46 , 65 , 66 as a follow-up to our work on the uracil moiety. Bazgir and coworkers 67 refluxed 6-aminouracils with different isatin derivatives in ethanol and p -TSA to get spiro[pyrimido[4,5- b ]quinoline-5,5′-pyrrolo[2,3- d ]pyrimidine]pentaones.…”

Preparation of Ion2+-COS/SA Multifunctional Gel Films for Skin Wound Healing by an In Situ Spray Method

“…The equilibrium swelling rate of the 1% COS + C group was significantly higher than that of the other groups, exhibiting a rapid water uptake (up to 12,000% at 2 h). Compared with the single-ion group, the introduction of Sr 2+ and Zn 2+ enhanced the stability of the gel films, which led to an increase in the cross-link density of the gel film fibers, resulting in a decrease in the swelling multiplier [26]. This may also be due to the fact that the SA in the multi-ionic gel films can partially dissolve in water and precipitate out during the swelling process, resulting in a decrease in the added mass of the gel films, which eventually leads to a decrease in swelling.…”

Tailored Tetrasubstituted Imidazole Carrying the Benzenesulfonamide Fragments as Selective Human Carbonic Anhydrase IX/XII Inhibitors

“…Many pharmacophores have been reported as a Zn binding groups that can fit/block the active site of CAs [5] . Among such pharmacophores are sulfonamides, hydroxybenzene, fullerenes, benzopyrone, thiobenzopyrone, uracil and boronic acids [3,5b] . Amongst these chemical pharmacophores, sulfonamide was the dominant and most effective group in both marketed and reported CAIs [6] .…”