View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector Ghorab et al. Chemistry Central Journal (2017) 11:32 DOI 10.1186/s13065-017-0258-4 RESEARCH ARTICLE Open Access Antimicrobial and anticancer activity of some novel fuorinated thiourea derivatives carrying sulfonamide moieties: synthesis, biological evaluation and molecular docking Mostafa M. Ghorab1,2*, Mansour S. Alsaid1, Mohamed S. A. El‑Gaby3*, Mahmoud M. Elaasser4 and Yassin M. Nissan5 Abstract Background: Various thiourea derivatives have been used as starting materials for compounds with better biological activities. Molecular modeling tools are used to explore their mechanism of action. Results: A new series of thioureas were synthesized. Fluorinated pyridine derivative 4a showed the highest anti‑ microbial activity (with MIC values ranged from 1.95 to 15.63 µg/mL). Interestingly, thiadiazole derivative 4c and coumarin derivative 4d exhibited selective antibacterial activities against Gram positive bacteria. Fluorinated pyridine derivative 4a was the most active against HepG2 with IC50 value of 4.8 μg/mL. Molecular docking was performed on the active site of MK-2 with good results. Conclusion: Novel compounds were obtained with good anticancer and antibacterial activity especially fuorinated pyridine derivative 4a and molecular docking study suggest good activity as mitogen activated protein kinase-2 inhibitor. Keywords: Isothiocyanate, Sulfonamide, Fluorinated thiourea, Antimicrobial and anticancer activity Background the increased hydrophobicity, and (v) the second small- Fluorinated compounds are intriguing for the develop- est atomic radius of the fuorine atom. Tese factors are ment of pharmaceuticals, agrochemicals, and materials, operative singly or sometimes cooperatively to afect the and thus, much efort has been exerted to develop more pharmacological properties of the fuorinated molecules general and efcient approaches for introducing fuorine [5]. Te majority of fuorinated drugs are constructed by atom(s) or fuoroalkyl group(s) into organic molecules fve- and six-membered nitrogen heterocycles containing [1–4]. Te unique properties of fuoro organic molecules fuorine, trifuoromethyl, difuoromethyl, fuoromethyl, may arise from the properties such as (i) the greatest elec- 2,2,2-trifuoroethyl, and pentafuoroethyl groups [6]. An tronegativity of fuorine, (ii) the largest strength of the increasing number of fuorinated antimitotic/antitumour carbon–fuorine bond, (iii) the hardness and the low van agents have now becoming available for cancer treat- der Waals interaction due to the low polarizability, (iv) ment. Te most widely used are the 5-fuoropyrimidines such as 5-fuorouracil (5-FU) and 5-fuoro-2\-deoxy- uridine (FdUrd) [7, 8], (Fig. 1). Te thiourea derivatives *Correspondence: [email protected]; [email protected]; represent one of the most promising classes of anticancer [email protected] 1 Pharmacognosy Department, College of Pharmacy, King Saud agents with a wide range of activities against various leu- University, P.O. Box 2457, Riyadh 11451, Saudi Arabia kemia and solid tumors [9–17]. Tey play an important 3 Department of Chemistry, Faculty of Science, Al-Azhar University role as anticancer agents because of their good inhibitory at Assiut, Assiut 71524, Egypt Full list of author information is available at the end of the article activity against protein tyrosine kinases (PTKs), [10–13] © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ghorab et al. Chemistry Central Journal (2017) 11:32 Page 2 of 14 Fig. 1 Fluorinated and thiourea anticancer agents human sirtuin type proteins 1 and 2 (SIRT1 and SIRT2), benzenesulfonamides 3a–e and 4a–d from readily avail- [14] topoisomerase II [15] and DNA repair synthesis able starting material to evaluate their antimicrobial and [16]. Furthermore, fuorinated aryl thioureas represent anticancer activity. a new class of potent anti-trypanosomal agents [18] and also a novel class of potent infuenza virus neuramini- Results and discussion dase inhibitors [19]. Tiocarlide is a pharmacologically Chemistry important thiourea drug that is used as a therapeutic Isothiocyanates are useful and widely used building agent in the treatment of tuberculosis [20] and Pheneth- blocks in the synthesis of nitrogen, sulfur and oxygen ylthiazoylthiourea (PETT) derivatives (LY73497 and heterocycles and organometallic compounds of aca- trovirdine HCl) [21, 22] have been discovered as potent demic, pharmaceutical and industrial interest [36]. Te inhibitors of HIV type 1, (Fig. 1). high electrophilicity and nucleophilicity associated with Literature survey revealed that sulfonamides are a sig- the carbon and sulfur atoms, respectively, of the isothi- nifcant class of compounds in medicinal and pharma- ocyanates and their extended π electron system make ceutical chemistry with several biological applications them unique precursors of a large variety of target mol- [23]. Today, they are widely used as antimicrobial agent, ecules. Consequently, many classes of fve and six-mem- chiefy because of their low cost, low toxicity and excel- bered nitrogen and sulfur heterocycles, either carrying lent activity against bacterial diseases [24]. Some impor- various substituents or fused with benzo or non-benzo tant sulfonamide derivatives used as carbonic anhydrase nuclei to interesting poly heterocycles, have been syn- inhibitors of commercial importance [25]. Tey are also thesized from isothiocyanates which is undoubtedly a efective for the treatment of urinary, intestine, and oph- landmark in organosulfur chemistry [37]. Te interme- thalmic infections, scalds, ulcerative colitis [26], rheu- diate, N-(2,6-dimethoxypyrimidin-4-yl)-4-isothiocy- matoid arthritis [27], male erectile dysfunction as the anatobenzenesulfonamide 2 used for the preparation of phosphodiesterase-5 inhibitor sildenafl-better known target compounds have been synthesized in high yield under its commercial name, Viagra [28], and obesity via thiophosgenation of sulfa-dimethoxazine 1 at room [29]. More recently, sulfonamides are used as an anti- temperature in the presence of dilute hydrochloric acid, cancer agent [30], as the antiviral HIV protease inhibi- according to literature procedure [38] (Scheme 1). tor amprenavir [31] and in Alzheimer’s disease [32]. Te synthesis of N-(2,6-dimethoxypyrimidin-4-yl)- Prompted by the above facts and in continuation of our 4-(3-(aryl) thio-ureido)benzenesulfonamides 3a–e is interest in biologically active compounds [33–35] we outlined in Scheme 2. Treatment of isothiocyanato ben- hereby report the synthesis of some novel of fuorinated zenesulfonamide 2 with a variety of fuorinated aro- N-(2,6-dimethoxypyrimidin-4-yl)-4-(3-(aryl)thioureido) matic amines in dry dioxane at refux temperature in Ghorab et al. Chemistry Central Journal (2017) 11:32 Page 3 of 14 Scheme 1 Synthesis of N‑(2,6‑dimethoxypyrimidin‑4‑yl)‑4‑isothiocyanato‑benzenesulfonamide 2 the presence of a catalytic amounts of triethylamine NMR showed two singlets at δ 3.64, 3.66 ppm which were furnished the novel fuorinated N,N-disubstituted thio- assigned for two methoxy protons, a singlet at δ 6.5 ppm ureas 3a–e in high yields (80–92%).Te structure of the assigned to the pyrimidine-H, two downfeld singlets at products 3a–e were established via inspection of their δ 11.8, and 12.4 ppm which were readily assigned to the spectral data. Tioureas 3a–e were confrmed by the HN(1) and HN(2) protons, in addition to the presence of absence of characteristic infrared absorption peak at SO2NH and aromatic protons (Scheme 3). −1 2000–2200 cm (N=C=S group). Also, the infrared of 3 is characterized by the presence of the NH, CN, thiocar- Antimicrobial evaluation bonyl (CS) and SO2 absorption bands. For example, the Te newly synthesized target compounds were evalu- 1H NMR of compound 3a showed two singlets at δ 3.81, ated for their in vitro antibacterial activity against Strep- 3.84 ppm which were assigned for two methoxy pro- tococcus pneumoniae and Bacillus subtilis as examples tons, a singlet at δ 5.9 ppm assigned to the pyrimidine- of Gram-positive bacteria and Pseudomonas aeruginosa H, two downfeld singlets at δ 11.8, and 14.0 ppm which and Escherichia coli as examples of Gram-negative bacte- were readily assigned to the HN(1) and HN(2) protons, ria. Tey were also evaluated for their in vitro antifungal in addition to the presence of SO 2NH and aromatic pro- potential against a representative panel of fungal strains tons. Te thiocarbonyl group of thiourea moiety was also i.e. Aspergillus fumigatus, and Candida albicans. Te observed in 13C-NMR. Te formation of thiourea 3a–e organisms were tested against the activity of solutions can be explained by the reaction pathway depicted in of concentrations (1 mg/mL) and using inhibition zone Fig. 2. diameter in mm as criterion for the antimicrobial activ- Te nucleophilic attack of the amino group of the aro- ity (agar well difusion method).