Development of Novel Indole-3-sulfonamide-heteroaryl Hybrids as Carbonic Anhydrase Inhibitors: Design, Synthesis and in-vitro Screening.

BACKGROUND: Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. Inhibition of isoforms IX and XII has induced potent anticancer effects. OBJECTIVE: A series of indole-3-sulfonamide-heteroaryl hybrid (6a-y) was synthesized and screened for the inhibition of human (h) hCA isoforms I, II, IX, and XII. METHODS: The synthesis of target compounds (6a-y) was carried out in multistep starting from 5-nitro indole as starting material by using classical reported reaction conditions. The steps involved are N-Alkylation Chlorosulfonation, amination, reduction, and finally amidation reaction. RESULTS: Amongst all the compounds (6a-y) synthesized and screened, 6l was found to be active against all the screened hCA isoforms, with Ki ranging 8.03 µM, 4.15 µM, 7.09 µM, and 4.06 µM respectively. On the other hand, 6i, 6j, 6q, 6s, and 6t were highly selective against tumor-associated hCA IX, and 6u was selective against both hCA II and hCA IX with moderate inhibitory activities under the range of 100 µM. These compounds showed good activity against the tumor-associated hCA IX and might be developed as future drug leads for anticancer drug discovery. CONCLUSION: These compounds may be useful as starting points for the design and development of more selective and potent hCA IX and XII inhibitors.

Semisynthetic Transformations on (+)-Boldine Reveal a 5-HT2A/2CR Antagonist.

Aporphine alkaloids have shown affinity for serotonin receptors (5-HTRs), and there has been a recent upsurge of interest in aporphines as 5-HT2CR ligands. 1,2,9,10-Tetraoxygenated aporphine alkaloids in particular have demonstrated good affinity for 5-HTRs. In continued efforts to understand the impacts of structural modification of the 1,2,9,10-tetraoxygenated aporphine template on affinity, selectivity, and activity at 5-HT2R subtypes, we used (+)-boldine (8) as a semisynthetic feedstock in the preparation of C-2-alkoxylated (+)-predicentrine analogues. Compound 10n, which contains a benzyloxy group at C-2, has been identified as a novel 5-HT2CR ligand with strong affinity (4 nM) and moderate selectivity versus 5-HT2BR and 5-HT2AR (12-fold and 6-fold, respectively). Compound 10n functions as an antagonist at 5-HT2A and 5-HT2C receptors. Computational experiments indicate that several hydrophobic interactions as well as strong H-bond and salt bridge interactions between the protonated amine moiety in 10n and Asp134 are responsible for the potent 5-HT2CR affinity of this compound. Furthermore, compound 10n displays favorable predicted drug-like characteristics, which is encouraging toward future optimization.

Design and synthesis of benzenesulfonamide-linked imidazo[2,1-b][1,3,4]thiadiazole derivatives as carbonic anhydrase I and II inhibitors.

A novel series of imidazothiadiazole-linked benzenesulfonamide derivatives (5a-t) was synthesized and subjected for screening against the four physiologically and pharmacologically relevant human carbonic anhydrase (hCA) isoforms: hCA I, II, VA, and IX. The compounds selectively inhibited hCA I and II over hCA VA and IX. Furthermore, among the two cytosolic isoforms, hCA II was more effectively inhibited as compared with hCA I. The most active compounds were 5o with K i = 0.246 µM and 5p with K i = 0.376 µM against hCA II, whereas compound 5f showed good inhibition against both hCA I and II with K i = 0.493 and 0.4 µM, respectively. This class of underexplored sulfonamides may be used to design isoform-selective CA inhibitors targeting enzymes of medicinal chemistry interest.

Structure based design, synthesis and activity studies of small hybrid molecules as HDAC and G9a dual inhibitors.

Aberrant enzymatic activities or expression profiles of epigenetic regulations are therapeutic targets for cancers. Among these, histone 3 lysine 9 methylation (H3K9Me2) and global de-acetylation on histone proteins are associated with multiple cancer phenotypes including leukemia, prostatic carcinoma, hepatocellular carcinoma and pulmonary carcinoma. Here, we report the discovery of the first small molecule capable of acting as a dual inhibitor targeting both G9a and HDAC. Our structure based design, synthesis, and screening for the dual activity of the small molecules led to the discovery of compound 14 which displays promising inhibition of both G9a and HDAC in low micro-molar range in cell based assays.