{Synthesis and SAR studies of pyrazole-3-carboxamides and -thioureides including chiral moiety: Novel candidates as antibacterial agents} J. Serb. Chem. Soc. 83 (7–8) 795–807 (2018) UDC 547.435+547.772:542.913:57– JSCS–5113 188:615.281’272 Original scientific paper 795 Synthesis and SAR studies of pyrazole-3-carboxamides and -3-carbonyl thioureides including chiral moiety: Novel candidates as antibacterial agents ISHAK BILDIRICI1, ADNAN CETIN2*, NURETTIN MENGES1 and YUSUF ALAN3 1Van Yuzuncu Yil University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Van, Turkey, 2Muş Alparslan University, Faculty of Education, Department of Science, 49250, Muş, Turkey and 3Muş Alparslan University, Faculty of Science and Arts, Department of Biology, 49250, Muş, Turkey (Received 13 March, revised 6 December 2017, accepted 14 February 2018) Abstract: A series of tetrasubstituted pyrazole-3-carboxamides (3a–c) and pyr- azole-3-carbonyl thioureides (6a–c) were synthesized and their structures char- acterized by IR, NMR and elemental analysis. The antibacterial potential against specific Gram-positive and Gram-negative strains and the antifungal activities of all novel compounds were investigated. Structure–activity relation- ships (SAR) studies and some theoretical parameters (ClogP, CMR, PSA and ESP) of the compounds were performed on these two pyrazole derivatives. Pyrazole-3-carboxylate ester 2 was used for the synthesis of the carboxamide derivatives. The reactions of pyrazole-3-carbonyl isothiocyanate 5 with appro- priate chiral amino alcohols were utilized for synthesizing the thioureide deri- vatives. Both of these types of pyrazole derivatives including a chiral moiety exhibited pronounced antibacterial activities. According to the present in vitro study, some of the promising compounds might be new candidates for a new generation of antibacterial drugs. Keywords: biological activity; chiral amino alcohols; pyrazole; heterocyclic compounds. INTRODUCTION Chiral structures are important target molecules in chemistry since they have significant properties, such as catalytic,1 biological,2 pharmaceutical,3 agricul- tural4 and industrial implications.5 Chiral properties have brought a third dim- ension to the all these fields of science. On the other hand, carboxamide deri- vatives bearing a chiral stereocentre have also extensive workspace. For example, chiral carboxamides were used as a transporter for drug in pharmaceuticals.6 * Corresponding author. E-mail: adnankimya@gmail.com https://doi.org/10.2298/JSC170313029B ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2018 SCS. 796 BILDIRICI et al. Furthermore, compounds having thiourea are known to exhibit various biological properties, such as antibacterial,7 antifungal,8 antitubercular,9 antithyroid,10 ant- helmintic,11 rodenticidal,12 insecticidal,13 herbicidal14 and plant growth regul- ator15 activities. However, some thiourea derivatives including chiral moiety not only can serve as catalysts16 for the synthesis of optically active compounds, but can also be employed as medicines.17–19 Studies on the biological activities of chi- ral thioureas are relatively rare and the reported studies showed that they have a broad spectrum of biological activities, such as anti-HIV,20 anticancer21 and anti- viral.22 Some of the biologically active chiral thiourea and amide derivatives are showed in Fig. 1. Since the beginning of this century, pyrazoles, which are an important scaffold of heterocyclic compounds, have increasingly drawn the atten- tion of researchers because of their wider range of properties, particularly for their biological activities. These compounds have been used in the development of agricultural products and in drug research since they have diverse biological activities.23,24 Some known activities, such as pharmaceutical, agricultural and biological activities of these compounds containing a pyrazole ring system in the structure can be listed as high antihyperglycemic,25 analgesic,26 inflammatory,27 antipyretic,28,29 anti-bacterial30 and antidepressant.31 Fig. 1. Some of the important examples of pyrazole, carboxamide and thiourea deri- vatives. They provided protection against plant pests,32 as insecticides33 and against fungal organisms.34 They were also found to be hypotensive35 and antican- cer.36,37 Compounds including synthetic pyrazoles, such as the anti-rheumatic Celecoxib, have been used in the treatment of inflammation38 and pain.39 Rimo- nabant has been used for the treatment of obesity,40 difenzoquat exerted lethal ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2018 SCS. SYNTHESIS OF NOVEL PYRAZOLE-BASED ANTIBACTERIAL AGENTS 797 effects against plant pests41 and tartrazine lemon yellow dye is widely used as a colouring agent for food in the UK and the USA42 (Fig. 1). Studies on the implications of the stereochemistry of antibacterial agents have high significance in medicinal chemistry.43 However, the antimicrobial and antifungal activities of pyrazole-3-carboxamides and 3-carbonyl thioureides con- taining a chiral stereocentre have not hitherto been reported in the literature. Recently the design, synthesis, and antimicrobial activity of a series of novel carboxamide and thioureide derivatives including the pyrazole scaffold were rep- orted.44 Encouraged by these successful efforts, we aimed both to expand this study by synthesis new pyrazole derivatives containing chiral moiety and to eval- uate the antimicrobial potential against various Gram-positive and Gram-negative strains and antifungal activities of these novel compounds. Moreover, structure– –activity relationships (SAR) studies were undertaken and some theoretical para- meters of these newly synthesized derivatives were investigated. EXPERIMENTAL Materials and equipment The 1H- and 13C-NMR spectra were recorded at 400 and 100 MHz, respectively, on a Bruker DRX-400 high performance FT-NMR spectrometer. The NMR spectra were obtained in solutions of DMSO-d6 and CDCl3. Analytical TLC of all reactions was performed on Merck prepared plates. The infrared spectra were recorded on a Shimadzu IR-470 spectro- photometer. The elemental analyses were obtained with a Carlo Erba Model 1108 apparatus. The optical rotations were taken on a PerkinElmer 341 Model polarimeter. Refraction indices were measured using an Atago Abbe refractometer. The mass spectrum was measured on Thermo Scientific TSQ-Quantum Access LC/MS spectrometers. Analytical and spectral data of the synthesized compounds are given in Supplementary material to this paper. Compounds 1 (m.p.: 202–204 °C) and 2 (m.p.: 180 °C) were obtained according to a previous study.44 General procedure for the synthesis of chiral pyrazole-3-carboxamides (3a–c) To compound 2 (0.404 g, 1.0 mmol) dissolved in methanol (5 mL) in the reaction vessel was added dropwise a solution of a chiral amino alcohol (1 mmol, 2-amino-2-phenylethanol, 2-amino-3-methyl-1-butanol and 2-amino-1-butanol, respectively) in methanol (5 mL) at room temperature over 2 h. After the addition, solid product had precipitated that was filtered and washed with diethyl ether. The obtained product was purified by silica gel column chromatography (n-hexane/ethyl acetate in 7:1 volume ratio). General procedure for the synthesis of chiral pyrazole-3-carbonyl thioureides (6a–c) Compound 1 (0.397 g, 1 mmol) was refluxed with an excess of SOCl2 at 80 °C for about 7 h. The excess SOCl2 was evaporated. The remaining oily product was purified in a dry ether/cyclohexane mixture. As a result, 4-benzoyl-1-(2,5-dimethylphenyl)-5-phenyl-1H-pyra- zole-3-carbonyl chloride (4, m.p.: 145 °C) was obtained, according to the literature.44 The resulting acylchloride compound (4, 1.0 mmol) was dissolved in anhydrous acetone (15 mL) and a solution of 1 mmol ammonium thiocyanate in acetone (5 mL) was added to the reaction vessel. The reaction mixture was refluxed in a round-bottom flask equipped with a condenser ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2018 SCS. 798 BILDIRICI et al. for 4 h. The solvent was evaporated and the residue was washed with diethyl ether. The solid product was filtered and then the crude product was crystallized from n-hexane/diethyl ether. Finally, 4-benzoyl-1-(2,5-dimethylphenyl)-5-phenyl-1H-pyrazole-3-carbonyl isothiocyanate (5, m.p.: 159–160.5 °C) was obtained.44 Compound 5 (0.219 g, 0.50 mmol) dissolved in anhydrous acetone (5 mL) was added dropwise to the appropriate chiral amino alcohol (1 mmol, 2-amino-2-phenylethanol, 2-amino-3-methyl-1-butanol and 2-amino-1-butanol, respectively) in acetone (5 mL). This mixture was kept at room temperature for 4–6 h, after which the reaction mixture was poured onto ice-cold water. The formed precipitate was filtered, dried and the product was purified by crystallization in diethyl ether/n-hexane. Microorganisms and antimicrobial assays Although the antimicrobial activities of the starting compounds 1 and 2 were previously investigated,44 their antimicrobial activities were examined again in order to compare together. All samples (1, 2, 3a–c, 5 and 6a–c) were separately tested against Enterobacter aerogenes ATCC 13048, Bacillus subtilis ATCC 6633, Staphylococcus aureus 6538, Bacillus megaterium DSM 32, Pseudomonas aeruginosa 9027, Klebsiella pneumoniae RSKK 574, Escherichia coli, Candida albicans, Yarrovia lipolytica and Saccaromyces cerevisiae ATCC 10231 fungi. All the bacterial and fungal strains examined in the present study were supplied by the Microbiology Laboratory of Muş Alparslan University (Turkey). Penicillin (10 mg), amikacin (30 mg), erythromycin (15 mg), rifampicin (5 mg) and ampicillin (10 mg) antibiotics were used as the reference drugs. The antimicrobial activities of the samples were determined by the well dif- fusion method.45,46 For this purpose, the bacterial and fungal strains were cultured overnight at 37 °C in nutrient agar and 25 °C in Sabouraud dextrose agar medium, respectively. 100 µL of suspensions of test microorganisms, containing 1×108 colony-forming units (CFU) per mL-1 of bacteria cells and 1×104 CFU mL-1 spores of fungal strains were spread on nutrient agar and Sabouraud dextrose agar medium, respectively. Subsequently, the medium was poured into a Petri dish on a horizontally levelled surface. After the medium had solidified, 9 mm diameter wells per dish were made in the agar medium. Then 0.005, 0.01 and 0.02 g mL-1 doses of 1, 2, 3a–c, 5 and 6a–c suspensions dispersed in DMSO as 50 mg mL-1 were loaded into the wells separately. The Petri dishes were incubated at 37 °C for 24 h for bacteria and at 25 °C for 48 h for fungal strains. The average diameters of the inhibition zones were measured by repeating the experiment at least three times. RESULTS AND DISCUSSION Chemistry In the present study, two series of new chiral derivatives, 3a–c and 6a–c, containing a 1,4,5-trisubstituted-pyrazole-3-carbonyl moiety attached to the chir- ality centre, were synthesized. Initially, 4-benzoyl-1-(2,5-dimethylphenyl)-5-phe- nyl-1H-pyrazole-3-carboxylic acid (1) was synthesized according to a newly published manuscript and the corresponding methyl 4-benzoyl-1-(2,5-dimethyl- phenyl)-5-phenyl-1H-pyrazole-3-carboxylate (2) was obtained by heating the pyrazole-3-carboxylic acid 1 and methanol with a catalytic amount of sulphuric acid.44 Then, these compounds were derivitized by amino alcohols, (R)- -2-amino-2-phenylethanol, (R)-2-amino-3-methyl-1-butanol and (R)-2-amino-1- -butanol, respectively. The chiral pyrazole-3-carboxamides compounds were syn- ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2018 SCS. SYNTHESIS OF NOVEL PYRAZOLE-BASED ANTIBACTERIAL AGENTS 799 thesized by means of the reaction between methylpyrazole-3-carboxylate 2 and chiral amino alcohols at room temperature (Scheme 1). As a result of this react- ion, different new chiral pyrazole-3-carboxamides 3a–c were obtained in overall yield 72–78 % (Scheme 1). Scheme 1. Synthesis of pyrazole-3-carbox- amides of chiral amines. All new synthesized compounds were confirmed by analytical and spectral data (see Supplementary material). In the case of compounds 3a–c, the correct structures were established by IR and 1H-NMR spectroscopies in which characteristic –NH absorption bands were observed at 3325–3210 cm–1 in the IR spectra. Protons of the hydroxyl signals and NH protons of amide group signals were observed at δ 3.53– –2.50 ppm and at δ 8.42–8.34 ppm in the 1H-NMR spectra, respectively. In order to incorporate potent active pharmacophores, such as pyrazole, thio- urea and chiral amino alcohols, in a single molecule, a series of chiral pyrazolo- -thiourea derivatives 6a–c were synthesized by the reactions of 4-benzoyl-1-(2,5- -dimethylphenyl)-5-phenyl-1H-pyrazole-3-carbonyl isothiocyanate (5) with the above-mentioned chiral amino alcohols (Scheme 2). Therefore, first 4-benzoyl-1- -(2,5-dimethylphenyl)-5-phenyl-1H-pyrazole-3-carbonyl chloride (4) was obtained by heating pyrazole-3-carboxylic acid (1) with excess SOCl2 and then compound 5 was synthesized by heating the pyrazole-3-carbonyl chloride with ammonium thiocyanate in acetone for about 5 h.44 The chiral thioureide com- pounds 6a–c were prepared by a basic chemical procedure. Thus 6a–c were syn- thesized by heating pyrazole-3-carbonyl isothiocyanate (5) and the corresponding chiral amino alcohol derivative for 4–6 h as outlined in Scheme 2 (overall yield 60–80 %). These types of heterocyclic compounds including chiral structures are not found in the literature to date. Structure elucidations of the compounds 6a–c were based on 13C-NMR spectroscopy. Benzoyl carbonyl (C=O) signals were ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2018 SCS. 800 BILDIRICI et al. observed at δ 196.8–194.3 ppm, thioamide (C=S) at δ 185.6–180.3 ppm and amide carbonyl (C=O) signals at δ 167.7–165.9 ppm. SOCl2 NH4SCN N N HO O Ph CH3 H3C O Ph N N Cl O Ph CH3 H3C O Ph N N N O Ph CH3 H3C O PhC S 1 4 5 NH2 OH R 6a-c N N O N H Ph N H S R HO H3C CH3 Ph O 6 R a -Ph b -CH(CH3)2 c - C2H5 Scheme 2. Synthesis of chiral substituted thiourea derivatives 6 via pyrazolecarbonyl isothiocyanate 5. Biology Antibacterial activity. The antimicrobial activities of 1, 2, 3a–c, 5 and 6a–c against Gram-positive bacteria bacteria (Bacillus subtilis ATCC 6633, Staphylo- coccus aureus 6538, Bacillus megaterium DSM 32) and Gram-negative bacteria (Enterobacter aerogenes ATCC 13048, Pseudomonas aeruginosa 9027, Kleb- siella pneumoniae RSKK 574 and Escherichia coli ATCC 25922) as expressed minimal inhibitory concentration (MIC). Representative inhibition zone images were showed in Fig. 2. No antifungal activities of the compounds were detected against fungal strains (Candida albicans, Saccharomyces cerevisiae and Yarrovia lipolytica ATCC 10231, data not shown). TABLE I. The zones of inhibition (mm) of the materials with antibiotics against bacterial strains (MIC in µg/mL) MIC: minimal inhibitory concentration values with SEM = 0.02, –: totally inactive (no inhibition) Cmpd. Dose µg/mL Bacteria Gram-positive bacteria Gram-negative bacteria B. sub- tilis S. aureus B. mega- terium E. aero- genes E. coli P. aeru- ginosa K. pneu- monia 1 5 12 – – – – – 15 10 13 – – – 12 14 15 20 14 – 13 13 16 17 16 2 5 14 12 12 12 14 14 12 10 10 – – 12 12 12 12 20 12 – 10 14 16 16 16 ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2018 SCS. SYNTHESIS OF NOVEL PYRAZOLE-BASED ANTIBACTERIAL AGENTS 801 TABLE I. Continued Cmpd. Dose µg/mL Bacteria Gram–positive bacteria Gram–negative bacteria B. sub- tilis S. aureus B. mega- terium E. aero- genes E. coli P. aeru- ginosa K. pneu- monia 3a 5 – – – – 10 – 10 10 14 14 15 12 16 12 15 20 19 20 16 19 20 21 19 3b 5 11 12 11 10 12 10 10 10 13 12 15 14 15 12 14 20 16 22 18 18 16 20 18 3c 5 12 – – 12 12 – – 10 15 11 11 16 15 12 11 20 16 17 17 18 18 19 15 5 5 – – – – 11 – 13 10 12 12 12 14 13 – 15 20 16 17 16 16 17 18 16 6a 5 14 – 13 – 13 13 12 10 16 15 16 12 15 18 16 20 18 18 19 19 18 20 18 6b 5 12 12 – 12 – – 12 10 15 14 15 15 17 13 14 20 18 18 18 20 18 17 19 6c 5 13 – 12 – 14 13 – 10 14 13 13 13 14 13 14 20 15 15 15 15 15 14 16 Positive controls Erythro- mycin 15 20 21 25 27 19 19 19 Amik- acin 30 14 10 – 10 13 – 16 Peni- cillin 30 21 18 16 16 18 9 19 Ampi- cillin 10 9 – 10 – – – 10 Rifam- picin – 9 – 10 – – – 10 The in vitro antimicrobial and antifungal activities of the compounds and positive controls were tested in a dose manner (5, 10 and 20 µg mL–1) against ten microorganisms (Table I). The current results indicated that the synthesized com- pounds showed a broad spectrum of antibacterial activities producing 10–22 mm zones of inhibition. Among the tested compounds, 3b and 6a exhibited the high- est antimicrobial activities. All tested compounds showed higher antimicrobial activity compared to amikacin and rifampicin, except compound 2. Compounds 3b and 6a had similar or higher antimicrobial activity compared to penicillin. ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2018 SCS. 802 BILDIRICI et al. Moreover, the obtained data indicated strong antibacterial activity of pyra- zole-3-carbonyl derivatives, i.e., 3a–c and 6a–c exhibited pronounced activity against B. subtilis, 3a and 3b exhibited pronounced activity against S. aureus, 3b, 3c, 6a and 6b exhibited pronounced activity against B. megaterium, 3a–c, 6a and 6b exhibited pronounced activity against E. aerogenes, 3a exhibited strong acti- vity against E. coli. 3a, 3b and 6a exhibited pronounced activity against P. aeru- ginosa. Compound 3b exhibited the highest antimicrobial activity against Gram- -positive bacteria, followed by 3a and 3b. With regards to Gram-negative bac- teria, compound 3a showed the highest antibacterial activity followed by 3b and 3c. Compound 6a–c showed similar antibacterial activities against Gram-positive and Gram-negative bacteria. The pattern of the antimicrobial activity potential was 6a > 6b > 6c for both of Gram-positive and Gram-negative bacteria. In gen- eral, all compounds had pronounced antimicrobial activities against the bacteria strains. However, S. aureus and B. megaterium seemed to be more resistant to the compounds and the tested positive controls than the other bacteria strains. There was a positive correlation between antimicrobial activity and the concentrations tested, as shown in Table I. All tested compounds were pyrazole derivatives with certain modifications. Among the tested compound groups, 3 and 6 had the highest antimicrobial acti- vities. The pronounced antimicrobial activities of compounds 3 and 6 might be explained by the presence of chiral amino alcohol moiety. Relatively higher anti- microbial activities of 3b and 6a might be due to the presence of isopropyl and phenyl groups. The structure–activity relationships (SAR) studies The synthesized compounds were tested against many different types of bac- teria and fungi. Three Gram-positive and four Gram-negative bacteria were applied and some important activities on the bacteria were found. Unfortunately, for all compounds, no inhibition was observed against any of the fungi. The main skeleton of synthesized molecule was 1-(2,5-dimethyl-phenyl)-4-benzoyl-5-phe- nylpyrazole. Changeable units were selected as ester (2), carboxamide (3a–c), thiocyanate (5) and thioureide (6a–c). All synthesized molecules were prepared at a concentration of 10 mM in DMSO. The molecules with chiral unit showed the best activity against all bacteria. Chiral molecules which have stereogenic centre are important structures because bioactive molecules usually involve the activities of enantiomers. Chiral molecules should play a dominant role in their interactions with bioactive substances. Moreover, they should be applied only to molecules that contain the stereogenic centre in close proximity to the bioactive centre of the molecule, as was the case with the synthesised compounds. Syn- thetic routes to chiral molecules can be properly turned from achiral structures. ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2018 SCS. SYNTHESIS OF NOVEL PYRAZOLE-BASED ANTIBACTERIAL AGENTS 803 Molecules having a chiral structure are synthesized by chiral transfer, using a chiral starting material such as chiral amino alcohol. The ester group should be a derivative with some more potent and suitable groups. For this reason, compound 2 was substituted by (R)-amino-alcohol deri- vatives to obtain compounds 3a–c. The most active derivative of them was found to be 3a, which bears a phenyl group, against all bacteria except for S. aureus and B. megaterium. It was found that a bulky group on the (R)-amino-alcohol affected the activity against bacteria. To clear this idea, some physicochemical parameters were calculated.47 Hence, hydrophobic (ClogP: calculated partition coefficient), steric (CMR: calculated molecular refractivity) and electronic (PSA: polar surface area) parameters for all the synthesized compounds were calcul- ated. The theoretical lipophilicity of 3a–c decreases from 3a to 3c and was cal- culated as 6.67, 6.14 and 5.77, respectively. Calculation of CMR and ClogP for 3a–c revealed that CMR and ClogP affect the antibacterial activity and increasing them has a positive impact on the biological activity. The worst activity was detected for 3c, which bears an ethyl group, for which the values for CMR and ClogP are 138.43 and 5.77, respectively (Table II). The polar surface areas for 3a–c were calculated and it was seen that there is no change for compounds 3a–c. TABLE II. Some theoretical parameters for the synthesized molecules Compound PSA / Å2 CMR / cm3 mol-1 ClogP 1 69.97 116.47 5.03 2 49.74 120.33 6.31 3a 82 153.7 6.67 3b 82 142.90 6.14 3c 82 138.43 5.77 5 62 129.83 6.90 6a 94 170 6.83 6b 94 159 6.38 6c 94 154 6.02 Thiocyanate group attached to the molecule 5 shown lower activities than 3a–c. On the other hand, activities of 5 on bacteria were moderate. Compounds 6a–c which have thiourea and (R)-amino-alcohol chains were tested against same bacteria and it was calculated that reactivity against bacteria decreased and the most potent molecule of compounds 6a–c was 6a which bears phenyl ring. Theoretical parameters of compound 6a–c were also shown that biological activity could be affected by increasing of CMR and ClogP (Table II). Moreover, although CMR and ClogP of 6c was very close to 3a, which has the best potent molecule, biological activity of 6c is lower in comparison to 3a. Decreasing of reactivity on bacteria have shown that (R)-amino-alcohol unit should be adjacent to the carbonyl group and there should be no any other chain between carbonyl and (R)-amino-alcohol groups. After SAR study, it was worthy to say that (R)- ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2018 SCS. 804 BILDIRICI et al. -amino-alcohol unit increase the biological activity against some Gram-(–) and Gram-(+) bacteria. The electrostatic potential (ESP) of 3a was investigated to understand its H- donor and -acceptor units and its total electronic surface. According to the ESP map, the oxygen atoms of the two carbonyl groups and of the alcohol group are H-acceptors and the alcohol group is an H-donor group (Fig. 3). Fig. 3. Electrostatic potential (ESP) of 3a. The proton of the amide group is less acidic than the others and due to this, this proton might not be a good candidate for proton donation. The rest of mole- cule showed the expected electronic potential and these surfaces are not worthy of discussion. CONCLUSIONS Within this study, a series of tetra-substituted pyrazole-3-carboxamides (3a– –c) and pyrazole-3-carbonyl thioureides (6a–c) binding a chiral amino alcohol were synthesized and their antibacterial and antifungal properties were investi- gated. The structure–activity relationships (SAR) studies and some theoretical parameters (ClogP, CMR, PSA and ESP) of these pyrazole-carboxamide and -thioureide derivatives were investigated. Compound series 3 and 6 exhibited superior antimicrobial activities among the tested compounds. The pronounced antimicrobial activities of compound series of 3 and 6 can be explained by the presence of a chiral amino alcohol moiety. The relatively higher antimicrobial activities of 3b and 6a might be due to the presence of isopropyl and phenyl groups. The present results indicated that the synthesized compounds were active in a broad spectrum against important human pathogenic microorganisms. There- fore, these compounds might be new candidates for efficient antibacterial agents. ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2018 SCS. SYNTHESIS OF NOVEL PYRAZOLE-BASED ANTIBACTERIAL AGENTS 805 SUPPLEMENTARY MATERIAL Analytical and spectral data of the synthesized compounds are available electronically at the pages of journal website: http://www.shd.org.rs/JSCS/, or from the corresponding author on request. Acknowledgements. The authors thank to the Management Unit of Scientific Research Projects of Muş Alparslan University (MSÜBAP) for financial support under Project MSÜ14- -EMF-G05. The authors thank Dr. Abdullah Dalar for his valuable comments and corrections in the antimicrobial section. И З В О Д СИНТЕЗА И SAR ИСПИТИВАЊЕ ПИРАЗОЛ-3-КАРБОКСАМИДА И 3-КАРБОНИЛ-ТИОУРЕИДА И ХИРАЛНИХ СТРУКТУРА: НОВИ КАНДИДАТИ ЗА АНТИБАКТЕРИЈСКЕ АГЕНСЕ ISHAK BILDIRICI1, ADNAN CETIN2, NURETTIN MENGES1 и YUSUF ALAN3 1 Van Yuzuncu Yil University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Van, Turkey, 2 Muş Alparslan University, Faculty of Education, Department of Science, 49250, Muş, Turkey и 3Muş Alparslan University, Faculty of Science and Arts, Department of Biology, 49250, Muş, Turkey Синтетисана је серија пиразол-3-карбоксамида (3a–c) и пиразол-3-карбохил-тиоуреида (6a–c), а добијеним дериватима структура је одређена IR, NMR и елементалном ана- лизом. Испитана је антибактеријска активност према специфичним Грам-позитивним и Грам-негативним сојевима бактерија и антифунгална активност свих нових синтетиса- них једињења. Урађена је анализа утицаја структуре на активност (structure–activity rel- ationships, SAR) и неких теоријских параметара (ClogP, CMR, PSA и ESP). За синтезу карбоксамидних деривата коришћен је пиразол-3-карбоксилатни естар 2. Реакцијом пиразол-3-карбонил-изотиоцијаната 5 и одговарајућих хиралних алкохола добијени су деривати тиоурее. Обе групе добијених једињења показују запажену антибактеријску активност. Према приказаном in vitro испитивању, неки од деривата могу бити канди- дати за даља испитивања антибактеријске активности. (Примљено 13. марта, ревидирано 6. децембра 2017, прихваћено 14. фебруара 2018) REFERENCES 1. J. He, S. Li, Y. Deng, H. Fu, B. N. Laforteza, J. E. Spangler, J. Q. Yu, Science 343 (2014) 1216 2. A. E. Rashad, A. H. Shamroukh, M. I. Hegab, H. M. Awad, Acta Chim. Slov. 52 (2005) 429 3. X. H. Liu, B. F. Ruan, J. Li, F. H. Chen, B. A. Song, H. L. Zhu, J. Zhao, Mini Rev. Med. Chem. 11 (2011) 771 4. B. S. Sekhon, J. Pest. Sci. 34 (2009) 1 5. R. A. 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