Novel 3-Amino-6-chloro-7-(azol-2 or 5-yl)-1,1-dioxo-1,4,2-benzodithiazine Derivatives with Anticancer Activity: Synthesis and QSAR Study

Abstract

Abstract:A series of new 3-amino-6-chloro-7-(azol-2 or 5-yl)-1,1-dioxo-1,4,2-benzodithiazine derivatives 5a-j have been synthesized and evaluated in vitro for their antiproliferative activity at the U.S. National Cancer Institute. The most active compound 5h showed significant cytotoxic effects against ovarian (OVCAR-3) and breast (MDA-MB-468) cancer (10% and 47% cancer cell death, respectively) as well as a good selectivity toward prostate (DU-145), colon (SW-620) and renal (TK-10) cancer cell lines. To obtain a deeper insight into the structure-activity relationships of the new compounds 5a-j QSAR studies have been applied. Theoretical calculations allowed the identification of molecular descriptors belonging to the RDF (RDF055p and RDF145m in the MOLT-4 and UO-31 QSAR models, respectively) and 3D-MorSE (Mor32m and Mor16e for MOLT-4 and UO-31 QSAR models) descriptor classes. Based on these data, QSAR models with good robustness and predictive ability have been obtained.

Novel convenient approach to 1,4,2-benzodithiazine-1,1-dioxides and 1,2,3-benzoxathiazine-2,2-dioxides

“…General. 1 H and 13 C NMR spectra were acquired on a Varian VXR 300, Varian VXR 400 and Bruker Avance DRX 500. Elemental analysis was carried out in the analytical laboratory of the Institute of Organic Chemistry, NAS of Ukraine.…”

“…1 Н-NMR (СDCl3, 300 MHz) δ 7.28 td, (J 7.6 Hz, J 1.2 Hz) 1Н (Н6), 7.38 td, (J 7.6 Hz, J 1.2 Hz) 1Н (Н7), 7.45 dd, (J 7.6 Hz, J 1.2 Hz) 1Н (Н5), 8.01 dd, (J 7.6 Hz, J 1.2 Hz) 1Н (Н8). 13…”

“…7,8 Recent extensive studies of derivatives incorporating a 1,4,2-benzodithiazine-1,1-dioxide moiety have revealed among them anti-HIV agents, 9 potent KATP channel openers, 10 compounds with antitumor 11 and significant cytotoxic activities against ovarian (OVCAR-3) and breast (MDA-MB-468) cancers as well as a good selectivity toward prostate (DU-145), colon (SW-620) and renal (TK-10) cancer cell lines. 12, 13 1,2,3-Benzoxathiazine-2,2-dioxides were prepared by reactions of 2-acylated phenols with chlorosulfonyl isothiocyanate 14 , sulfamoyl chloride 15,16 or sulfamide 17 (O-C-C-C + S-N cyclizations). Known methods for the synthesis of 1,4,2-benzodithiazine-1,1-dioxides are based on reactions of 2halogenosulfonamides with isothiocyanates, 18 dithiocarbamates 10 (N-S-C-C + C-S cyclizations) or [2+2]cycloaddition of S-aryldithiocarbamates with chlorosulfonyl isothiocyanate followed by C-arylsulfonylation (S-C-C + C-N-S cyclizations), 19 and reactions of 2-mercaptoarylsulfonamides with dialkyl carbonates or phenacyl bromides (S-C-C-S-N + C cyclization).…”

Theoretical calculations of molecular descriptors for anticancer activities of 1, 2, 3-triazole-pyrimidine derivatives against gastric cancer cell line (MGC-803): DFT, QSAR and docking approaches

“…Realizing that successful treatment of cancer patients remains serious concerns and/or challenges for the researchers worldwide. Thus, theoretical calculations of molecular descriptors as well as simulations of drug-like molecules with protein receptors are essentials for the prediction of the bioactivity and potency/efficacy of such molecules (Chill et al, 2003;Pogorzelska et al, 2015;Elshakre et al, 2020). Also, knowing the stable conformation, binding free energy and nonbonding interactions of the drug-like molecule in the active gouge of the protein receptor will help in understanding the phymacokinetic of the drug interactions in the system ( Sled z and Caflisch, 2018;Marquina et al, 2019;Melge et al, 2019).…”

Statistical Analysis of the Impact of Molecular Descriptors on Cytotoxicity of Thiourea Derivatives Incorporating 2-Aminothiazole Scaffold

“…These electronic indexes have been successfully applied in describing and predicting the toxicity of oleoylamides, 2) 3-styryl-2H-chromenes, 3) benzodithiazine derivatives. 4) The aim of the study is to optimize a cytotoxic effect of 11 thiourea derivatives (listed in Table 1) towards the MT-4 cells in terms of chemical descriptors that are derived from electronic structure calculation. The research was extented and for the most active compounds (6 compounds-CC 50 <10 µM) the cytotoxic activity against three cancer cell lines (CCRF-CEM, WIL-2NS, CCRF-SB) was determined.…”