Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity**

Abstract

Mitochondrial respiratory complex II (CII), also known as succinate dehydrogenase, plays a critical role in mitochondrial metabolism. Known but low potency CII inhibitors are selectively cytotoxic to cancer cells including the benzothiadiazine‐based anti‐hypoglycemic diazoxide. Herein, we study the structure‐activity relationship of benzothiadiazine derivatives for CII inhibition and their effect on cancer cells for the first time. A 15‐fold increase in CII inhibition was achieved over diazoxide, albeit with micromolar IC50 values. Cytotoxicity evaluation of the novel derivatives resulted in the identification of compounds with much greater antineoplastic effect than diazoxide, the most potent of which possesses an IC50 of 2.93±0.07 μM in a cellular model of triple‐negative breast cancer, with high selectivity over nonmalignant cells and more than double the potency of the clinical agent 5‐fluorouracil. No correlation between cytotoxicity and CII inhibition was found, thus indicating an as‐yet‐undefined mechanism of action of this scaffold. The derivatives described herein represent valuable hit compounds for therapeutic discovery in triple‐negative breast cancer.

Nickel Pincer Complexes Catalyzed Sustainable Synthesis of 3,4-Dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxides via Acceptorless Dehydrogenative Coupling of Primary Alcohols

“…1 H NMR (400 MHz, DMSO): δ 8.86 (d,J = 4.4 Hz,1H),8.33 (d,J = 7.9 Hz, 1H), 8.14 (t, J = 7.2 Hz, 1H), 8.00−7.74 (m, 4H), 7.54 (dd, J = 7.9, 3.5 Hz, 1H), 7.23 (s, 1H), 6.85−6.55 (m, 1H), 5.85 (s, 1H). 13 C{ 1 H} NMR (100 MHz, DMSO): δ 144.0, 140.0, 133.2,132.3,131.0,130.6,127.1,124.0,122.0,121.1,117.3,116.7,2,4]thiadiazine 1,1-Dioxide (3r). 28 The title product was synthesized according to the general procedure, from using 2-aminobenzenesulfonzamide (172.20 mg, 1.0 mmol) and thiophene-2-methanol (114.16 mg, 1.0 mmol), white solid (yield: 74% and 198.08 mg).…”

In vitro antitumor activity, molecular dynamics simulation, DFT study, ADME prediction, and Eg5 binding of enastron analogues

“…38 Several families of compounds have been described in the literature showing potent cytotoxic activity against human cancer cell lines which include diarylisoxazole, 39 sulfonamide 40 and benzothiadiazine. 41 In this context and to develop new active antimitotic agents, we evaluated a series of benzothiadiazinone dioxide against human cancer cell lines, including LCL B cells (PRI), chronic myelogenous leukaemia cells (K562) and T-lymphoma cells (JURKAT) using MTT assay. 42 Chlorambucil (CLB) was used as a reference.…”

Selective Carbonic Anhydrase IX and XII Inhibitors Based Around a Functionalized Coumarin Scaffold

“…Addition of halide substitution to the coumarin ring results in decreased activity to inhibit CA II, IX and XII (compounds 9b, 9c, 9d and 9i) compared to hydroxyl substitution. (Huwaimel et al, 2021;Huwaimel et al, 2022) Converting the 7-hydroxy in the coumarin ring to 7-diethylamino (9g) increases activity to inhibit CA IX with Ki = 13.9 nM compared to AAZ which possesses a Ki of 25 nM. Addition of a second chlorine to the coumarin ring (9d) lead to a decrease in activity to inhibit CA II, IX and XII compared with a single chlorine (9b Table 3.…”