Structure Determination and Quantum Chemical Analysis of 1,3-Dipolar Cycloaddition of Nitrile Imines and New Dipolarophi
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tructure Determination and Quantum Chemical Analysis of 1,3-Dipolar Cycloaddition of Nitrile Imines and New Dipolarophiles and POM Analyses of the Products as Potential Breast Cancer Inhibitors T. A. Farghalya,b,*, I. M. Abbasa, W. M. I. Hassana,c, M. S. Lotfya, N. T. Al-Qurashid, and T. Ben Haddae a
Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613 Egypt b
c
Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah Almukkarramah, 21514 Saudi Arabia
Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, 21589 Saudi Arabia d
e
Department of Basic Science, University College in Adam, Umm Al-Qura University, Makkah Almukkarramah, 21514 Saudi Arabia
Laboratoire Chimie Matériaux, FSO, Université Mohammed 1ER, Oujda, 60000 Morocco *e-mail: [email protected]; [email protected] Received January 31, 2020; revised February 12, 2020; accepted February 18, 2020
Abstract—The 1,3-dipolar cycloaddition of nitrile imines to 11-aryl-4-(arylmethylidene)-1,2,3,4,11,11a-hexahydrodibenzo[b,e][1,4]thiazepines possessing exocyclic C=C and endocyclic C=N bonds as dipolarophilic sites showed site selectivity, depending on the type of C-substituent in the nitrile imine. 1,3-Dipolar cycloaddition of C-aryl nitrile imines occurred selectively to the exocyclic C=C bond, whereas the endocyclic C=N bond was involved in the cycloaddition with C-ethoxycarbonyl nitrile imines. A combination of total energy and molecular orbital plots for the highest occupied and lowest unoccupied molecular orbitals was used to verify the proposed reaction mechanisms and stereoselectivity. Some of the isolated products exhibited moderate to good antitumor activity. The results of POM analysis of the relative cytotoxicity of these new derivatives in comparison to Doxorubicin are also reported. Keywords: hydrazonoyl chlorides, site selectivity, regioselectivity, antitumor activity, pharmacophore sites, Petra/Osiris/Molinspiration (POM) analyses
DOI: 10.1134/S1070428020070210 INTRODUCTION In recent years, chemoselectivity in 1,3-dipolar cycloadditions of nitrile imines to multifunctional dipolarophiles possessing two or more different dipolarophilic sites has attracted the interest of several research groups [1]. For example, the cycloaddition of nitrile imines to compounds I and II (Fig. 1) which contain exocyclic C=C and endocyclic C=N double bonds was found to occur selectively to the exocyclic C=C double bond to give the corresponding spiro pyrazole derivative [2, 3]. Contrary to the foregoing reports, it was found that the cycloaddition of nitrile imines to III and IV (Fig. 1) occurred selectively to the
endocyclic C=N double bond to yield fused 1,2,4-triazoles [4, 5]. Both spiro pyrazoles and fused 1,2,4-triazoles have been reported to exhibit a wide range of biological activities [6, 7]. Quantum chemical calculations play an important role in elucidation and confirmation of the actual structure of heterocyclic compounds and stereoselectivity of the reactions. In this article,
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