1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 z Medicinal Chemistry & Drug Discovery Synthesis and Antibacterial Evaluation of New Pyrimidyl N- Ciprofloxacin Derivatives Majid Mokaber-Esfahani, [a, b] Hossein Eshghi,* [a] Marzieh Akbarzadeh, [a] Mostafa Gholizadeh, [a] Yahya Mirzaie, [c] Mohammad Hakimi, [c] and Jalil Lari [c] Herein, nucleophilic substitution reaction of pyrimidine deriva- tives on piperazine in ciprofloxacin resulted in the formation of new pyrimidyl N-ciprofloxacines. These compounds were prepared at room temperature, at conventional heating and under microwave irradiation conditions. Results indicated microwave condition as a green approach in comparison with room temperature and at conventional heating condition leads to higher yields and very short reaction times. 1 H, 13 C-NMR, FT- IR, Mass spectroscopy and CHN analysis were used to character- ize all the synthesized products. Meanwhile, the antibacterial activity of these new compounds against gram-positive and gram-negative bacteria was investigated and showed more activities for two new N-ciprofloxacin derivatives than cipro- floxacin. Introduction Microwave-assisted organic synthesis complies with the princi- ples of green chemistry that has attracted increasing interest in drug discovery. These reactions, which were assisted to excellent chemical/thermal stability and good solvating ability, displayed significant merits by their reduced reaction time, the simplicity of processing, improved yields, low pollution and eco-friendly method [3À6] . Heating reactions with oil bath are the most common method for the preparation of organic compounds. This method is time-consuming and with the making of a hot surface on the reaction vessel often results in decomposition of materials over time and therefore, low efficiency is inevitable. These problems and the priority of chemical industries to do reactions with low times and high yields have resulted in using microwave energy. In microwave method, microwave irradi- ations pass through the walls of the reaction vessel and the reactants and solvent heat directly, and then conversion of electromagnetic radiation to heat in a chemical reaction and selective absorption cause an acceleration of reaction. In this strategy, an increase in uniform temperature in the sample and decrease of by-products or product decomposition were showed [9À11] . Quinolones have emerged as molecules with useful properties that have gained considerable attention on medical chemists due to their biological activity. They are synthetic antibacterial compounds with a 4-quinolone skeleton. Interaction of quinolone with two essential bacterial type II topoisomerases, DNA gyrase and DNA topoisomer IV that both are require for cell growth and division, causes inhibition of their DNA synthesis. Therefore quinolones introduced as antibacterial compounds. Nalidixic acid was the first quinolone that used as an antibacterial agent and then modification on its basic structure (quinolone) produced new compounds with improved antibacterial activity [15À18] . Fluoroquinolones, includ- ing ciprofloxacin and ofloxacin, are important antibacterial agents used in various infectious diseases [19] . However, the growing of fluoroquinolones usage has impacted against the gram-negative bacteria, while they acted comparatively moder- ate against gram-positive bacteria. Also, some of them function as anticancer and anti-HIV inhibitors [22,23] . Nowadays, for the discovery of new antimicrobial agents, direct manipulation of the structure of available antibacterial agents is a practical approach to improve antimicrobial efficacy. Although fluoro- quinolones have major application for clinical use, researchers attempt to improve their characters in the hospital applications via the structural modification of their framework. It has been found that C-7 substituent of fluoroquinolones is responsible for drug-enzyme interactions and the control of cell perme- ability. In this regard, substitutions on piperazine ring in 6- fluoro-7-piperazinylquinolone compounds, which carried out through nucleophilic aromatic substitution reaction on the corresponding halides produced new fluoroquinolones. In this work, we synthesized pyrimidyl N-ciprofloxacines by nucleophilic substitution H atom of piperazine in ciprofloxacin with various pyrimidine moieties (Scheme 1). We used three strategies for the synthesis of these compounds, first at room temperature, then with microwave irradiation and finally in conventional heating. eventually antibacterial activity of new products was reported. However, despite a good yield of the first reaction, its application was limited due to the above problems and advantages of microwave irradiation including [a] Dr. M. Mokaber-Esfahani, Prof. H. Eshghi, Dr. M. Akbarzadeh, Prof. M. Gholizadeh Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran E-mail: heshghi@um.ac.ir [b] Dr. M. Mokaber-Esfahani Department of Chemistry, Faculty of Science, Gonbad Kavous University, Gonbad Kavous, Iran [c] Dr. Y. Mirzaie, Prof. M. Hakimi, Dr. J. Lari Department of Chemistry, Payame Noor University, 19395-3697 Tehran, Iran Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.201901924 Full Papers DOI: 10.1002/slct.201901924 1 ChemistrySelect 2019, 4,1–5 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim