ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 7, pp. 1047–1052. © Pleiades Publishing, Ltd., 2019. 1047 One-Pot CuO-Catalyzed Green Synthesis of N(N′)-Arylbenzamidines as Potential Enzyme Inhibitors M. B. Taj a–c ,* A. Raheel a , W. Alelwani d , N. Babteen d , S. Kattan e , A. Alnajeebi e , M. Sharif b , R. H. Ahmad f , Abbas c , A. Hazeeq c , S. A. Tirmizi a , and H. B. M. Ali c a Department of Chemistry, Quaid-e-Azam University, Islamabad, Pakistan *email: drbabartaj@gmail.com b Department of Chemistry, Islamia University, Bahawalpur, Pakistan c Department of Chemistry, University of Malaya, Kuala Lampur, Malaysia d Department of Biochemistry, Faculty of Science, University of Jeddah, Saudi Arabia e College of Applied Medical Sciences, Taibah University, Yanbu, Saudi Arabia f Department of Nano Science and Technology, National Centre for Physics, Islamabad, Pakistan Received September 21, 2018; revised May 8, 2019; accepted May 15, 2019 Abstract—Ten N(N′)-arylbenzamidines were synthesized in 60–77% yield by one-pot microwave-assisted reaction of the corresponding N-arylbenzamides with aniline or ammonia in the presence of copper(II) oxide powder. The synthesized compounds were evaluated in vitro for inhibitory activity against several enzymes, namely acetylcholinesterase, butyrylcholinesterase, lipoxygenase, α-glucosidase, urease, and reverse transcrip- tase. Some compounds showed very good acetylcholinesterase and butyrylcholinesterase inhibitory activity. N′-(1,3-Benzothiazol-2-yl)- and N′-(1,3,4-thiadiazol-2-yl)benzamidines were the most active α-glucosidase inhibitors with IC 50 values of 134.2 and 244.57 μM, respectively. N′-(1,3-Benzothiazol-2-yl)benzamidine also inhibited urease. Most of the obtained compounds showed inhibitory activity against reverse transcriptase (anti- HIV activity), presumably due to intermolecular hydrogen bonding, good solubility, and hydrophilicity. Keywords: N-substituted benzamidines, acetylcholinesterase, lipoxygenase, α-glucosidase, reverse transcriptase. In addition to enormous applications in materials chemistry and organic synthesis [1, 2], amidines con- stitute an influential social class of organic compounds that are often used in the synthesis of a variety of drugs [3], including noforymycine, dasatinib, and pentami- dine, because of their variable binding characteristics and low toxicity [4]. Amidines are organic bases and important building blocks in the synthesis of hetero- aromatics such as quinazolines [5] and benzimidazoles [6]. N-Substituted benzamidines have found valuable synthetic applications for the preparation of imino- peptides [7, 8], antibiotics [9], purines [10], and novo- cain derivatives [11]. Furthermore, benzamidine nu- cleus is a peculiar inhibitor of trypsin [12] and related serine proteases [12]; benzamidine derivatives act as antimicrobial and antiparasitic agents [13], and they have been used in the treatment of various diseases, including Pneumocystis pneumonia, antimony-resis- tant leishmaniasis [13], and human African trypanoso- miasis [14] for over fifty years. N-Substituted benz- amidines are known to bind nucleic acids; such activity is vitally essential to their mechanism of action in some disease models. This property of N-substituted benzamidines has been recognized for some time, and inflection of long amidine-containing compounds has been planned for sequence-specific targeting of both RNA and DNA [15]. Many synthetic scenarios leading to N-substituted benzamidines have been reported in the literature [16–20]. However, the use of corrosive reagents, high reaction temperature, low yield of the products, and laborious procedures made these meth- odologies less advantageous. Therefore, the synthesis of N-substituted benzamidines is still a matter of im- mense interest. In view of the synthetic and pharma- ceutical importance of benzamidines, herein we report a facile synthesis of N-substituted benzamidines via electrophilic activation of benzamides and their inhibi- tory potential against several enzymes. DOI: 10.1134/S1070428019070224