untitled ISSN 215 Synthes complex Wasfi Abo 1 Department of 2 Department of 3 Department of 4 Department of * Corresponding Tel.: +964.78098 ARTICLE IN DOI: 10.5155/e Received: 26 No Received in rev Accepted: 02 Ja Published onlin Printed: 31 Mar KEYWORDS Synthesis Schiff base Sulfonamide Metal complexe Modeling studie Antimicrobial a 1. Introduct It has compounds s complexes th drugs can b metal ion [1 catalysts, int stabilizers. biological antidiabetic, corrosion an amides were be used sys agents again Sulfur l components possess man antiepileptic complexes a and growing Some of platin (anti 53‐2249 (Print) sis, antimi xes of Sch oud Al‐Maso f Physiology and Ch f Microbiology, Coll f Chemistry, College f Basic Sciences, Co g author at: Depart 830756. Fax: +964. FORMATION eurjchem.7.1.102‐1 ovember 2015 vised form: 02 Janu anuary 2016 ne: 31 March 2016 rch 2016 S es es activity tion been reporte show greater a han as free com be enhanced up 1]. Schiff bases termediates in A number o activities inc antitumor, a nd anti‐inflam e the first drugs stematically as st various disea ligands are w of biological ny applications c drugs among as chemotherap g area of researc the metal base cancer drug), E / ISSN 2153‐225 htt Europ icrobial a hiff base d oudi 1,*, Rana hemistry, College of lege of Veterinary, e of Education for P llege of Dentistry, U tment of Physiology .40.412714. E‐mail 106.1374 uary 2016 ed that the activity when ad mpound. The e pon co‐ordinat s are used as organic synthe f Schiff’s bas luding antiba antiproliferative mmatory activit s found to act s s preventive a ases [6]. widespread am transition met s such as diure g others [7‐9] peutic drugs ha ch in recent tim ed drugs alread silverderma uropean Journal Europ 57 (Online)  20 tp://dx.doi.org/ pean Jo Journal web ctivity an derived fr a Adnan Faa f Veterinary, Univer University of Basra Pure Sciences, Unive University of Basra y and Chemistry, Co l address: almasoud ABSTRACT Palladium(II) sulfonamide sulfonamide yield. Treatm and 3, respect against Esch Additionally, Candida albic Molecular mo interactions. Cite this: Eur. biologically dministered as efficacy of the s tion with a su pigments and esis and as po se molecules acterial, antif e, anticancer, ties [2‐5]. Sul selectively and and the therap mong co‐ordin tal complexes w etic, antiglaucom . The use of as become a vi me. dy in market ar (silver compl l of Chemistry 7 pean Journal of C 016 Atlanta Pub 10.5155/eurjche ournal bpage: www. nd modell om sulph az 2, Rafid Hm rsity of Basrah, Bas ah, Basrah 61001, I ersity of Basrah, Ba h, Basrah 61001, Ir ollege of Veterinary di59@yahoo.com ( and cobalt(II (Sulfonamide with 2‐hydroxy ment of compoun tively. The synth erichia coli, B the compounds cans. Some com odeling studies w . J. Chem. 2016, active metal sulpha uitable dyes, olymer show fungal, anti‐ phon‐ could peutic nation which ma or metal ibrant re cis‐ ex of sulf com rep plat anti syn from anti 2. E 2.1. Phi spe Uni wer with Mas spe (1) (2016) 102‐ Chemistry lishing House LL em.7.1.102‐106. of Che .eurjchem.co ing studie honamide medan Al‐A srah 61001, Iraq Iraq asrah 61001, Iraq raq y, University of Bas W. Al‐Masoudi). ) complexes o drug) were p y‐1‐naphthaldeh nd 1 with CoCl2 hesized compou Bacillus cereus, were tested for mpounds exhibi were performed 7(1), 102‐106 fadiazine for mplex of sulfadi orted the m tinum(II) of 3, icancer agents nthesize some n m sulfonamide imicrobial agen Experimental . Instrumentat Melting points lip Harris melti ectra were reco icam SP3‐300 s re recorded on h TMS as an in ss spectra (EI ectrometers (Fin ‐106 LC ‐ All rights re .1374 emistry m es of som drug in v Asadi 3 and H rah, Basrah 61001, of Schiff base repared by co yde gave the S .6H2O and PdCl nds were screen Salmonella sp r antifungal activ ited good antib and showed hy skin burn tr iazine for anim metal complex 5‐dimethyl‐2’‐p [11]. The aim new metal com drug and study nts. tion s are uncorrect ing point appar orded in the ra spectrometer u 400 MHz spec nternal standar I, 70 eV) wer nnegan MAT, U served ‐ Printed y e new me vitro Hazim Saad J , Iraq. derived from onvenient meth Schiff base comp 2yielded new m ned for their ant pp. and Staphy vity against Asp bacterial and an ydrogen binding eatment), flam al burn) [10]. S xes of palla pyrimidyl)pyra m of the presen mplexes of Schif y of their biolog ted and were m ratus and unco nge 4000‐200 using KBr discs ctrometers (Bru rd and on the δ re recorded o SA). d in the USA etal Jabbar 4 4‐aminobenzen hod. Reaction pound 1 in goo metal complexes tibacterial activi ylococcus aureu pergillus niger an ntifungal activit and hydrophob mmazine (zinc Saha et al. have adium(II) and azole as potent nt work was to ff base derived gical activity as measured on a rrected. The IR cm‐1 on a Pye‐ s. NMR spectra uker, Germany) δ scale in ppm. on MAT 8200 ne of od 2 ty us. nd ty. bic c e d t o d s a R ‐ a ) . 0 Al‐Masoudi et al. / European Journal of Chemistry 7 (1) (2016) 102‐106 103 Scheme 1 2.2. Synthesis 2.2.1. Synthesis of Schiff‐base, 4‐{[(2‐hydroxynaphthalen‐1‐ yl)methylidene]amino}benzenesulfonamide (1) To a solution of sulfonamide(1.37, 2.00 mmol) in EtOH (20 mL) was added ethanolic solution of 2‐hydroxy‐1‐naphth‐ aldehyde (0.76 g, 2.00 mmol) followed by addition of catalytic amount of glacial acetic acid drop wise and the mixture was heated under reflux for 3 h. The reaction mixture was then cooled in an ice bath and the crude product thus obtained was collected by filtration, further purified by recrystallization from ethanol gave compound 1 (Scheme 1). Color: Yellow. Yield: 78%. M.p.: 276‐278 °C. FT‐IR (KBr, , cm‐1): 3420‐3335 (OH, NH), 3082‐3063 (CH‐aromatic), 1622 (C=C), 1602 (C=N). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 15.46 (s, 1H, OH), 9.70 (s, 1H, CH=N), 8.52‐7.01 (m, 10H, Ar‐H), 7.43 (s, 2H, NH2). 13C NMR (400 MHz, DMSO‐d6, δ, ppm): 171.5 (C, C‐OH), 156.9 (C‐ CH=N), 147.2 (C, Ar‐C), 141.9 (C, Ar‐C), 138.1 (C, Ar‐C), 133.5 (C, Ar‐C), 129.5 (C, Ar‐C), 128.7 (C, Ar‐C), 127.6 (C, Ar‐C), 127.2 (C, Ar‐C), 124.2 (C, Ar‐C), 122.6 (C, Ar‐C), 121.2 (C, Ar‐C), 121.0 (C, Ar‐C), 109.3 (C, Ar‐C). MS (EI, m/z (%)): 326 (M+, 100). 2.2.2. Synthesis of cobalt complex (2) Schiff base ligand 1 (5 mmol) was dissolved in 20 mL of ethanol solution, then 2.5 mmol of the CoCl2.6H2O was added. A stirrer was inserted and the reaction mixture was heated to about 75‐80 °C for 2 h. The precipitate that was formed filtered and washed severally with ethanol and dried in an oven at about 70 °C to yield cobalt complex 2 (Scheme 1). Color: Pale‐green. Yield: 73%. M.p.: 195‐196 °C. FT‐IR (KBr,, cm‐1): 3395‐3325 (NH), 3065, 3024 (CH‐aromatic), 1627 (C=C), 1608 (C=N). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 9.68 (s, 2H, 2CH=N), 8.53‐7.11 (m, 20H, Ar‐H), 7.45 (s, 4H, 2NH2). 13C NMR (400 MHz, DMSO‐d6, δ, ppm): 170.8 (2C, C‐O), 159.50 (2C, CH=N), 147.2‐109.3 (C‐Ar). MS (EI, m/z (%)): 709 (M+, 100). 2.2.3. Synthesis of palladium complex (3) Palladium(II) complex was prepared in the same manner using PdCl2 in place of CoCl2.6H2O to yield palladium complex 3 (Scheme 1). Color: Yellow‐brown. Yield: 77%. M.p.: 174‐176 °C. FT‐IR (KBr, , cm‐1): 3380‐3317 (NH), 3057, 3023 (CH‐ aromatic), 1619 (C=C), 1605 (C=N). 1H NMR (400 MHz, DMSO‐ d6, δ, ppm): 9.52 (s, 2H, 2CH=N), 8.44‐7.08 (m, 20H, Ar‐H), 7.47 (s, 4H, 2NH2). 13C NMR (400 MHz, DMSO‐d6, δ, ppm): 167.6 (2C, C‐O), 152.3 (2C, CH=N), 144.6‐112.9 (C‐Ar). MS (EI, m/z (%)): 758 (M+, 100). 2.3. Antimicrobial activity The synthesized compounds were screened in vitro for their antibacterial activity against: Escherichia coli, Salmonella spp., Staphylococcus aureus, Bacillus cereus. Additionally, the compounds were tested for antifungal activity against Aspergillus niger and Candida albicans using the paper disc‐ agar diffusion technique on Muller Hinton agar as a culture media for antibacterial activity [12]. The test compounds were dissolved in DMSO solvent and recommended concentrations (50, 100 and 200 μg/mL) were used in the disc‐agar diffusion technique. Antibiotic drug ciprofloxacin and nystatin were used as control for bacteria and fungi, respectively. Petri plates containing 20 mL of Mueller Hinton Agar were used for all the bacteria tested. Aspergillus niger and Candida albicans strains were cultivated in Sabouraud dextrose agar. Sterile Whatman no. 1 filter paper disks (6 mm in diameter) impregnated with the solution in DMSO of the test was placed on the Petri plates. A paper disk impregnated with dimethylsulfoxide was used as negative control. The plates were incubated for 24 h at 37 °C in the case of bacteria and 72 h that 27 °C for fungi. The inhibition zone diameters were measured in millimeters. The bacteria and fungi were supplied from department of Microbiology, College of Veterinary Medicine, University of Basrah. 2.4. Molecular modeling analysis The molecular docking was performed using SYBYL‐X 1.1 and the docking results were shown by PyMOL [13]. Our molecular docking analysis of the new analogues based on the modelling study which was performed to understand the binding mode of these analogues with the aspartate aminotransferase (ATT) of E. coli [14] binding pocket (PDB code: 1ahg, [15]). 104 Table 1. HSQC 3. Results an 3.1. Chemist Treatmen 1‐naphthalde acetic acid u 1 in 78% yie ions; Co and Scheme 1. Th assigned by t The IR regions and regions. The the presence 1 attributed symmetrical spectra conf stretching w addition, th assigned to t In the 1H hydroxy pro 15.46 for com compounds 2 the singlets a imino proton 7.01 ppm we data for Schiff‐bas 1H (ppm) 9.70 8.50 7.95 7.93 7.81 7.80 7.55 7.38 7.00 nd discussion try nt of 4‐aminobe ehyde in ethan under reflux aff eld, Scheme 1. T Pd in 2:1 ratio he structures o the IR and 1H, 1 spectra displa characteristic b spectra for all e of broad stron to ν(O‐H) an and unsymmet firm the presen with a sharp r e bands at th the C=C aromat H NMR spectra oton were reso mpound 1, whi 2 and 3. In the at δ 9.70, 9.68 a ns (CH=N). The ere attributed to Al‐M se of sulphanamide Fig enzenesulfonam nol and catalyt forded the desi The ligand 1 re o forming comp of the synthesiz 3C and 2D NMR ayed common bands in the fin compounds w ng bands in the nd ν(N‐H) for trical for compo nce of the azom region around he region 162 ic group. of synthesized onated as singl ich this signal d 1H NMR spectr and 9.52 ppm w e multiplets at o the aromatic p Masoudi et al. / E e (L). 4- SH2N O O 13C (p 156.9 121.0 138.0 128.0 121.5 130.0 129.0 125.0 122.0 gure 1. HSQC‐NMR mide with 2‐hyd tic amount of g red imine deriv eacted with me plexes in good y zed compounds R and mass spec features in c nger print and were characteriz rang 3420‐331 r ligand 1 an ound 2 and 3. T methine group ( 1608‐1605 cm 27‐1619 cm‐1 compounds 1‐ let at the regi disappear in com ra of compound were assigned f t the regions δ protons. European Journal 2- 6- 1- 3- 5- N C ppm) R of Schiff base der droxy‐ glacial vative etal(II) yields, s were ctra. ertain other zed by 17 cm‐ d NH The IR (‐C=N) m‐1. In were ‐3, the ons δ mplex ds 1‐3, for the 8.53‐ at δ for pre The cros gro aro and atom com (CH with corr and ppm can 3.2. vitr disc in m use anti test aur l of Chemistry 7 ( 1 2 3 4 4a 5 67 8 8a HO CH rived from sulfona In the 13C NMR δ 171.5, 170.8 the aromatic c sence of CH=N e 1H, 13C HSQC ss peak at δH/ up (N=CH). Th matic rings su d other position ms of the arom The gradient mpound 1 rev H=N) at δ 9.70 p h C‐1 of the n relation with th d the last one w m. Other correl n be assigned in . Antibacterial The synthesiz ro antibacterial c‐agar diffusion mm [11]. The ed as a control ibacterial activ ted against tw reus and Bacillu (1) (2016) 102‐1 Assign C, H (C C, H (5) C, H (4) C, H (3‐ C, H (2‐ C, H (7) C, H (8) C, H (6) C, H (3) mide. R spectra of com and 167.6 ppm carbon atom (C group around δ NMR spectrum /δC = 9.70/15 us, the correlat uch as δH/δC = ns can be assign atic ring, Table selected 1H, 1 vealed two 1,3J ppm showed tw naphthyl ring he aromatic car with the aromati lations betwee Figure 2. l and antifunga zed compounds l and antifunga n technique by m antibiotics, cip against bacteri vity of the sy wo Gram posit us cereus) and 06 nment H=N) ) ) ‐ , 5‐) ‐ , 6‐) ) ) ) ) mpounds 1‐3, t m, respectively, C‐O). The spectr δ 156.9, 159.5 a m of Schiff bas 6.9 ppm due tion of protons 8.52/121.0, 7. ned to the proto 1, Figure 1. 13C HMBC‐NMR JC,H. Thus, the wo 1,3JC,H correla at δ 160.3 pp rbon atom C‐6’ ic carbon atom n protons and al activity s were screene al activities, us measuring the rofloxacin and a and fungi, re ynthesized com tive bacteria ( two Gram neg the resonances were assigned ra revealed the and 152.3 ppm. se 1 showed a to azomethine s and carbon in .95/138.0 ppm ons and carbon R spectrum of imino proton ations: first one m, the second at δ 109.3 ppm C‐1’ at δ 147.2 d carbon atoms ed for their in sing the paper inhibition zone nystatin were spectively. The mpounds were (Staphylococcus gative bacteria s d e . a e n m n f n e d m 2 s n r e e e e s Table 2. Antiba Compound 1 2 3 Ciprofloxin Table 3. Antifu Compound 1 2 3 Nystatin Figure 3. Dock atom of the phe as phenyl group (Escherichia 100 and 20 effected the g as culture m antimicrobia All these against all th acterial activity of Diameter of inhi E. coli 50 µg/mL 100 µg/m ‐ 18 ‐ ‐ ‐ ‐ 10 ungal activity of som Diameter of inhi A. niger 50 µg/mL ‐ ‐ 15 ked conformation o enolresidue. It also p of Tyr65 with ph coli and Salmo 00 μg/mL usin growth of micr media for antib al activity are sh e compounds e he bacterial spe Al‐Masoudi et some Schiff base a ibition zone in mm mL 200 µg/mL 22 ‐ 7 me Schiff base and ibition zone in mm 100 µg/mL ‐ ‐ Fig of compound 1 sh o exhibits hydroph henol aromatic ring onella spp.) at a ng DMSO as a obes. Mueller H acterial activity hown in Tables xhibited mode cies. However, al. / European Jo nd metal complex m for different m B. cereus 50 µg/mL 100 µg/m ‐ 20 ‐ ‐ ‐ ‐ 12 d metal complex co m for different m L 200 µ ‐ 7 gure 2. HMBC‐NMR howing two hydrog hobic interactions b g of AAT of E. coli e concentration solvent, whic Hinton agar was y. The results 2 and 3. rate to good ac Schiff base 1 ha ournal of Chemis compounds. microbial species mL 200 µg/mL 22 18 ‐ mpounds. microbial species µg/mL R of Schiff base der gen bonds: Tyr151 between phenyl rin enzyme residues. of 50, ch not s used of the ctivity ad the high inac com S. ce wor Gra anti stry 7 (1) (2016) Salmonella spp. 50 µg/mL 100 µg/m ‐ ‐ ‐ ‐ 7 9 24 C. albicans 50 µg/mL ‐ ‐ ‐ 12 rived from sulfona N S O N HO 1 with one oxygen ng of Tyr151 and a hest activity ag ctive against E mpound 3 whic ereus and Salm rth noting that am positive and ifungal activity 102‐106 mL 200 µg/mL 9 ‐ 10 100 µg/m 20 ‐ ‐ amide. O N S O NH2 H O H Tyr151 O HO2C H Tyr65 n atom of SO2 grou aromatic ring of th gainst E. Coli an E. Coli and Sa h showed a mo onella spp. but t all compound d negative bact y of the synth S. aureus 50 µg/mL 100 µg/m ‐ ‐ ‐ ‐ 7 12 10 mL 200 22 18 ‐ O NH2C H Ser104 up, Ser104 OH gro he phenylsulfonam nd B. Cereus, bu almonella spp., oderate activity inactive agains ds have activit teria. On the o hesized compo 105 mL 200 µg/mL 18 15 15 0 µg/mL oup with hydrogen mide moiety as well ut compound 2 inaddition to y against E. coli, st B. cereus. It is ty against both other hand, the ounds showed n l 2 o , s h e d 106 Al‐Masoudi et al. / European Journal of Chemistry 7 (1) (2016) 102‐106 moderate activity towards all the fungal species such as Aspergillus niger and Candida spp., except compounds 1 and 2 which exhibit no activity against Aspergillus niger. 3.3. Molecular modeling analysis Compound 1 has been selected for the docking modeling study, since its binding energy score ‐8.3, with indicating a selectivity of phenyl azomethin and phenol groups in their binding to the enzyme pocket Figure 3. As shown in Figure 3, the aromatic ring of compound 1 was fitted into an aromatic rich sub‐pocket surrounded by the aromatic side chains of Tyr151 and Tyr65, in addition to two hydrogen bondings. The synthesized molecule was located in the middle of the binding pocket, anchoring the oxygen atom of the SO2 group in a favourable position for hydrogen bonding with the OH group of Tyr151, in addition to a hydrogen bonding between the oxygen atom of phenolic group and hydroxyl group for Ser104 of the aspartate amino transferase (AAT) enzyme. Overall, the combination of hydrophobic interaction and‐stacking appears to govern the binding of compound 1 with AAT of E. coli [16]. 4. Conclusion In conclusion, some new cobalt(II) and palladium(II) complexes containing sulphanamide were prepared by convent method. The antimicrobial activity was evaluated against four bacterial strains and two fungal species. The synthesized compounds exhibited good antibacterial and antifungal activities. Molecular modeling studies were performed, showing the hydrogen bindings and hydrophobic interactions. Acknowledgements We thank Miss Anka Friemel of Chemistry Department, University of Konstanz, Germany for the NMR experiments. We are also grateful to the Departments of Physiology and Microbiology, College of Veterinary Medicine, Basrah University, Iraq for providing the facilities. References [1]. Robin, R. C.; Melissa, K. R.; Johanna, M. B.; Joshwa, C. S.; Scott, N. Trans. Metal Chem. 2005, 30, 411‐418. [2]. Shivakumar, K.; Shashidhar; Reddy, P. V.; Halli, M. B. J. Coord. Chem. 2008, 61(14), 2274‐2287. [3]. Shi, L.; Mao, W. J.; Yang, Y.; Zhu, H. L. J. Coord. Chem. 2009, 62(21), 3471‐3477. [4]. Gupta, M. K.; Har, L. S.; Varshney, S.; Vareshny, A. K. Bioinorg. Chem. Appl. 2003, 1(3‐4), 309‐320. [5]. Hahn, R. C.; Moratoconciecao, Y. T.; Santos, N. L.; Ferreira, J. F.; Hamdan, J. S. Mycoses 2003, 46, 342‐347. [6]. Henry, R. J. Bacteriol. Rev. 1943, 7(4), 175‐262. [7]. Mohamed, G. G.; Carmen, M. S. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2007, 66, 949‐958. [8]. Rudzinski, W. E.; Aminabhavie, T. M.; Biradar, N. S.; Patil, C. S. Inorg. Chim. Acta. 1982, 67, 177‐182. [9]. Raveendran, R.; Pal, S. J. Organomet. Chem. 2007, 692(4), 824‐830. [10]. Orvig, C.; Abrams, M. J. Chem. Rev. 1999, 99, 2201‐2203 [11]. Saha, N.; Muherjee, D. Inorg. Chem. Acta 1987, 137, 161‐166. [12]. Shah, S. N; Basser, M. A. Asian J. Pharm. Clin. Res. 2012, 5(3), 146‐149. [13]. Zhan, P.; Liu, X.; Li, Z.; Fang, Z.; Pannecouque, C.; De Clercq, E. Chem. Biodivers. 2010, 7, 1717‐1727. [14]. Onuffer, J. J.; Ton, B. T.; Kleent, I.; Kirsch, J. F. Protein Sci. 1995, 4, 1743‐1749. [15]. Seeliger, S.; de Groot, B. L. J. Computer‐Aided Mol. Design 2010, 24, 417‐422. [16]. Al‐Masoudi, W. A.; Mohmmed, A. L.; Abass, W. H.; Al‐Masoudi, N. A. Eur. J. Chem. 2015, 6(2), 127‐130.