Novel indolin-2-one-based sulfonamides as carbonic anhydrase inhibitors: Synthesis, in vitro biological evaluation against carbonic anhydrases isoforms I, II, IV and VII and molecular docking studies.

Herein we present the design, synthesis, and biological evaluation of three different series of novel sulfonamides (3a-f, 6a-f and 9a-f) incorporating substituted indolin-2-one moieties (as tails) linked to benzenesulfonamide (as zinc anchoring moieties) through aminoethyl or (4-oxothiazolidin-2-ylidene)aminoethyl linkers. The synthesized sulfonamides were evaluated in vitro for their inhibitory activity against the following human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IV and VII. All these isoforms were inhibited by the sulfonamides reported here in variable degrees. hCA I was inhibited with KIs in the range of 42-8550.9 nM, hCA II in the range of 5.9-761 nM; hCA IV in the range of 4.0-2069.5 nM, whereas hCA VII in the range of 13.2-694 nM. Molecular docking studies were carried out for some of the tested compounds within the hCA II active site, allowed us to rationalize the obtained inhibition results.

Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents.

A hybrid pharmacophore approach was adopted to design and synthesize new series of isatin-pyridine hybrids. All the newly prepared hybrids (5a-o, 8 and 11a-d) were in vitro evaluated for their anti-proliferative activity against three human cancer cell lines, namely HepG2 hepatocellular carcinoma, A549 lung cancer and MCF-7 breast cancer. Compound 8 emerged as the most active member against HepG2 cell line (IC50 = 2.5 ± 0.39 µM), with 2.7-fold increased activity than the reference drug, doxorubicin (IC50 = 6.9 ± 2.05 µM). Whilst, compound 11c was found to be the most potent counterpart against A549 and MCF-7 cell lines with IC50 values of 10.8 ± 1.15 and 6.3 ± 0.79, respectively. The weightiness of the utilization of non-cleavable linker, as the chalcone linker, and simplification of the first group, was explored via the SAR study. Furthermore, a QSAR model was built to explore the structural requirements controlling the cytotoxic activities. Notably, the predicted activities by the QSAR model were very close to those experimentally observed, hinting that this model could be safely applied for prediction of more efficacious hits comprising the same skeletal framework. Finally, a theoretical kinetic study was established to predict the ADME of the active hybrids.