untitled European Journal of Chemistry 5 (3) (2014) 481‐487 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2014 Eurjchem Publishing ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.5.3.481‐487.1054 European Journal of Chemistry Journal homepage: www.eurjchem.com Synthesis and antimicrobial evaluation of some 1,2,4‐triazolo[1,5‐a]pyridine, pyrimidine sulfonamides and sulfinyl derivatives Fatma Fakhry Abdel‐Motaal a and Mohamed Abd‐Elmonem Raslan b,* a Botany Department, Faculty of Science, Aswan University, 81528 Aswan, Egypt b Chemistry Department, Faculty of Science, Aswan University, 81528 Aswan, Egypt *Corresponding author at: Chemistry Department, Faculty of Science, Aswan University, 81528 Aswan, Egypt. Tel.: +2.097.3480450. Fax: +2.097.3480450. E‐mail address: raslanma47@yahoo.com (M.A. Raslan). ARTICLE INFORMATION ABSTRACT DOI: 10.5155/eurjchem.5.3.481‐487.1054 Received: 18 March 2014 Received in revised form: 20 April 2014 Accepted: 24 April 2014 Online: 30 September 2014 KEYWORDS Several new substituted sulfonamides and sulfinyl compound derivatives were obtained by the reaction of 2‐thioxo‐1,2,4‐triazolo[1,5‐a]pyridine and pyrimidine thiol derivatives with (2‐ chloromethyl)benzimidazole and/or (2‐chloromethyl)benzooxazole. Structures of the newly synthesized products have been deduced on the basis of spectral and analytical data. The synthesized compounds were screened for their antimicrobial activity. Sulfinyl Pyrimidine Benzooxazole Sulfonamides Benzimidazole Triazolopyridine 1. Introduction Heterocycles containing sulfonamide moieties have attracted obvious attention due to their significant biological properties and their role as pharmacohores [1‐6]. Studies have shown that sulfonamide compounds were used as antibacterial [7‐9], antifungal [9,10], antiviral [11], anticancer [12], ant‐ inflammatory, analgesic [13‐15], and antibacterial agents [16]. Also, a wide variety of benzimidazole derivatives have been described for their chemotherapeutic importance [17‐23] and oxazole derivatives play very important role in the manufac‐ turing process of various biologically active drugs as anticancer, antimicrobial, antidiabetic and antiobesity [24,25]. A large number of heterocyclic compounds containing pyridine rings are associated with diverse pharmacological properties such as anticancer, antimicrobial, anticonvulsant, antifungal, antiviral, anti‐HIV, and anti‐microbacterial activities [26,27]. The pyridine ring is one of the most well‐known systems among the naturally occurring heterocycles, pyridine and fused pyridine moieties present in numerous natural products such as quinoline and isoquinoline alkaloids and nicotine and its analogs [28]. In the recent years, the biological properties of 1,2,4‐ triazoles have been widely investigated. They were shown to be effective as anti‐inflammatory, antibacterial, anticonvulsant, dephlogisticate, anti‐depressant, antifungal, anticancer, antibacterial properties, antipyretic, and antifungal agents [29‐ 32]. Pyridyl methyl sulfinyl benzimdizole derivatives such as omeprazole, rebeprazole, lansoprazole, pantoprazole, esomp‐ tazol are the drug of choice for the acid related gastrointestinal disorders. These drugs act by inhibiting the proton pump (H/K ATPase) which involved in the acid secretion in the stomach [33]. Moreover, pyrimidine moiety have been widely used in the design of biologically active agents, structure containing such units often play an essential role owing to their wide range of biological activity particularly in cancer and virus research [34,35]. Coumarins are a structural scaffold in the numerous natural products and one of the well‐known oxygen containing heterocycles showing a variety of biological applications [36‐ 38]. As a part of our ongoing studies we now describe synthesis of new 1,2,4‐triazolo[1,5‐a]pyridine, pyrimidine sulfonamides, sulfinyl derivatives and in connection with our previous studies [39‐47], on poly‐functionally heteroaromatic compounds, we reported here 1,2,4‐triazolo[1,5‐a]pyridine, pyrimidine, and coumarin with benzimidazole, and/or benzooxazole moiety in single molecular framework with evaluation of their biological activities that we are expected to have enhanced biological activities which is the goal of our study. 482 Motaal and Raslan / European Journal of Chemistry 5 (3) (2014) 481‐487 N N H H N O CO2Et Ar NC S + X N Cl 1. CH3ONa 2. Stiring, RT N N H N O CO2Et Ar NC S N X N N N O CO2Et Ar NC S N XS Ar1 O O 1 2 a, X = NH; b, X = O 3 a, X = NH; b, X = O 4 a, X = NSO2C6H4CH3-p; b, X = O H2O2N N N O CO2Et Ar NC S N XS Ar1 O O 5 a, X = NSO2C6H4CH3-p; b, X = O O Ar = C6H4OCH3-p Ar1 = C6H4CH3-p CH2Cl2 1. TsCl, Pyridine 2. Stiring, RT Scheme 1 2. Experimental 2.1. Instrumentation Melting points were determined on a Gallen‐kamp apparatus and are uncorrected. The IR spectra were recorded on Shimadzu FT‐IR 8101 PC infrared spectrophotometer. The 1H NMR spectra were determined in DMSO‐d6 at 300 MHz on a Varian Mercury VX 300 NMR spectrometer using TMS as an internal standard. Mass spectra were measured on a GC/MS‐ QP1000 EX spectrometer at 70 Ev. Elemental analyses were carried out at the Microanalytical Center of Cairo University. Ethyl 6‐cyano‐7‐(4‐methoxyphenyl)‐5‐oxo‐2‐thioxo‐1,2,3,5‐ tetrahydro[1,2,4]triazolo[1,5‐a]pyridine‐8‐carboxylate [48] (1) and 2‐(chloromethyl)benzimidazole or 2‐(chloromethyl) benzooxazole (2a,b) were prepared according to the reported literature [49‐51] (Scheme 1). 2.2. Synthesis 2.2.1. General procedure for synthesis of compounds 3a, 3b, 9 and 13 Sodium (25 mmol) was added to a solution of compound 1, 8 and 12 (20 mmol) in anhydrous MeOH (100 mL) and the mixture was stirred vigorously for 1 h, 2‐(chloromethyl) benzimidazole and/or 2‐(chloromethyl)benzooxazole (2a,b) (20 mmol) was added portion‐wise to the mixture and left to stirring for 3 days. The reactions mixture was triturated was ice water containing HCl. A yellow to brown precipitate was formed, filtered off and washed was water several times, dried and recrystallized from the appropriate solvent (Scheme 1‐3). Ethyl 2‐((1H‐benzo[d]imidazol‐2‐yl)methylthio)‐6‐cyano‐3,5‐ dihydro‐7‐(4‐methoxyphenyl)‐5‐oxo‐[1,2,4]‐triazolo[1,5‐a] pyri dine‐8‐carboxylate (3a): Recrystallized from DMF/ H2O. Color: Brown. Yield: 69%. M.p.: 195‐196 C. FT‐IR (KBr, , cm‐1): 3375, 3268 (2NH), 3115 (CH), 2905, 2850 (CH) 2212 (CN), 1685 (C=O), 1664 (C=O), 1628 (C=N), 1586 (C=C). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.17 (t, 3H, CH3), 3.76 (s, 3H, OCH3), 4.03 (q, 2H, CH2), 4.64 (s, 2H, SCH2), 8.64 (s, 1H, NH, D2O‐exchangeable), 6.62 (d, 2H, Ar‐H), 7.31 (d, 2H, Bz‐H), 7.75 (d, 2H, Bz‐H), 7.80 (d, 2H, Ar‐H), 11.43 (s, 1H, NH, D2O‐exchangeable). 13C NMR (75 MHz, CDCl3, δ, ppm): 168.8 (C‐7), 167, 164.5 (2C=O), 158.9 (C‐ ArOCH3‐p), 152.1, 147.2 (C‐triazole), 142.6 (C‐imidazole), 116.4 (CN), 115.7 (C‐6), 109.4 (C‐8), 114.5, 115.2, 123.3, 124.7, 127.9 (C‐Ar), 62.1 (CH2), 55.8 (OCH3), 33.4 (CH2S), 13.8 (CH3). MS (EI, m/z (%)): 500 (M+, 52). Anal. calcd. for C25H20N6O4S: C, 59.99; H, 4.03; N, 16.79. Found: C, 59.95; H, 3.99; N, 16.73%. Ethyl 2‐((benzo[d]oxazol‐2‐yl)methylthio)‐6‐cyano‐3,5‐ dihydro‐7‐(4‐methoxyphenyl)‐5‐oxo‐[1,2,4]‐triazolo[1,5‐a]pyridi ne‐8‐carboxylate (3b): Recrystallized from DMF/ H2O. Color: Pale brown. Yield: 56%. M.p.: 182 C. FT‐IR (KBr, , cm‐1): 3263 (NH), 3119 (CH), 2910, 2846 (CH) 2204 (CN), 1689 (C=O), 1668 (C=O), 1632 (C=N); 1579 (C=C). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.14 (t, 3H, CH3), 3.78 (s, 3H, OCH3), 4.09 (q, 2H, CH2), 4.61 (s, 2H, SCH2), 8.89 (s, 1H, NH, D2O‐exchangeable), 6.64‐7.84 (m, 8H, Ar‐H). MS (EI, m/z (%)): 501 (M+, 62). Anal. calcd. for C25H19N5O5S: C, 59.87; H, 3.82; N, 13.96. Found: C, 59.91; H, 3.81; N, 13.94%. 3‐(2‐((1H‐Benzo[d]imidazol‐2‐yl)methylthio)‐6‐ethoxypyrimi din‐4‐yl)‐2H‐chromen‐2‐one (9): Recrystallized from dioxane. Color: Pale yellow. Yield: 73%. M.p.: 175 C. FT‐IR (KBr, , cm‐ 1):3279 (NH), 3119 (CH), 2896, 2847 (CH), 1691 (C=O), 1627 (C=N); 1582 (C=C). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.27 (t, 3H, CH3), 3.82 (q, 2H, CH2), 4.39 (s, 2H, SCH2), 6.79 (s, 1H, H‐ 5), 7.03‐7.11 (m, 8H, Ar‐H), 8.05 (s, 1H, H‐4chromen), 11.13 (s, 1H, NH, D2O‐exchangeable). 13C NMR (75 MHz, CDCl3, δ, ppm): 169.4 (C‐4pyrimidine), 169.2 (C‐2pyrimidine), 165 (C=O), 162.7 (C‐ 6pyrimidine), 151.8 (C‐8a chromen), 146.5 (C‐4chromen), 143.5 (C‐ 2imidazole), 139.6 (C‐3a, 8aimidazole), 107.3 (C‐5pyrimidine), 128.9, 127.6, 125.7, 123.2, 121.3, 122.1, 115.5 (C‐Ar), 64.1 (CH2), 34.9 (CH2S), 14.7 (CH3). MS (EI, m/z (%)): 430 (M+, 86). Anal. calcd. for C23H18N4O3S: C, 64.17; H, 4.21; N, 13.01. Found: C, 64.04; H, 4.16; N, 13.05%. Ethyl 2‐(((8‐(ethoxycarbonyl)‐6‐cyano‐3,5‐dihydro‐7‐(4‐ methoxyphenyl)‐5‐oxo‐[1,2,4]triazolo[1,5‐a]pyridine‐2‐ylthio) methyl)‐sulfanyl)‐6‐cyano‐3,5‐dihydro‐7‐(4‐methoxyphenyl)‐ 5‐oxo‐[1,2,4]‐triazolo[1,5‐a]pyridine‐8‐carboxylate (13): Recrys‐ tallized from dioxane. Color: Pale brown. Yield: 38%. M.p.: 155 C. FT‐IR (KBr, , cm‐1): 3275, 3262 (NH), 3119 (CH), 2215 (CN), 1689 (C=O), 1669 (C=O), 1635 (C=N); 1584 (C=C). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.23 (t, 6H, 2CH3), 3.77 (s, 6H, 2OCH3, 4.11 (q, 4H, 2CH2)), 4.61 (s, 2H, SCH2), 8.74, 8.78 (brs, 2H, 2NH, D2O‐exchangeable), 6.71‐6.79 (m, 4H, Ar‐H), 7.22‐7.27 (m, 4H, Ar‐H). Motaal and Raslan / European Journal of Chemistry 5 (3) (2014) 481‐487 483 Scheme 2 MS (EI, m/z (%)): 752 (M+, 15). 13C NMR (75 MHz, CDCl3, δ, ppm): 167.3, 161.5 (4C=O), 153.7 (2C‐2triazole), 159.3 (2C‐ ArOCH3‐p), 152.1 (2C‐7), 146.8 (2C‐8a), 115.9 (2CN), 108.9 (2C‐8), 128.1, 125.2, 115.4, 114.3, 109.2 (12C‐Ar), 61.9 (2CH2), 55.8 (2OCH3), 19.7 (‐SCH2S‐), 14.1 (2CH3). Anal. calcd. for C35H28N8O8S2: C, 55.84; H, 3.75; N, 14.89. Found: C, 55.79; H, 3.81; N, 14.86%. 2.2.2. Synthesis of 3‐(3,3‐bis(methylthio)acryloyl)‐2H‐ chromen‐2‐one (7) Prepared according to procedure [52], to a solution of NaH (0.45 mol) in benzene (150 mL), a solution of compound 6 (0.2 mol), CS2 (0.2 mol) in dry DMF (100 mL) was added in portions during 1 h. The reaction mixture was kept under stirring for 3 h. followed by addition of methyl iodide (0.4 mol) in portions with cooling. The reaction mixture was allowed to stand at room temperature for 6 h. and then refluxed for further 4 h. After cooling, it pour into ice water with stirring. The precipitate obtained was filtered off and washed was cold water several times and dried (Scheme 2). Recrystallized from DMF/EtOH. Color: Buff crystals. Yield: 63%. M.p.: 92 C. FT‐IR (KBr, , cm‐1): 3114 (CH), 1697 (C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 2.35 (s, 6H, 2CH3), 6.21 (s, 1H, C=H), 7.09‐ 7.35 (m, 4H, Ar‐H), 8.43 (s, 1H, H‐4chromen). MS (EI, m/z (%)): 291 (M+, 29). Anal. calcd. for C14H12O3S2: C, 57.51; H, 4.14. Found: C, 57.49; H, 4.04%. 2.2.3. Synthesis of 3‐(6‐ethoxy‐2‐mercaptopyrimidin‐4‐yl)‐ 2H‐chromen‐2‐one (8) Prepared according to procedure [52], to a solution of the sodium ethoxide ((0.04 mol) of Na in 75 (mL) of EtOH) was added compound 7 (0.02 mol) and the reaction mixture was refluxed for 10‐12 h. The solvent was removed under reduced pressure and the residue was treated with glacial acetic acid (15 mL) to dissolve the sodium salt of pyrimidine and refluxed for 15 min. The reaction mixture was poured on crushed ice and the precipitate was filtered off and washed was cold water several times and dried (Scheme 2). Recrystallized from DMF. Color: Brownish‐yellow. Yield: 51%. M.p.: 215‐217 C. FT‐IR (KBr, , cm‐1): 3145 (NH), 1165 (C=S), 3119 (CH), 1695 (C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.28 (t, 3H, CH3), 4.29 (q, 2H, CH2), 6.81 (s, 1H, H‐5), 7.11‐7.34 (m, 4H, Ar‐H), 8.05 (s, 1H, H‐4chromen), 8.65 (brs, 1H, SH, D2O‐exchangeable). MS (EI, m/z (%)): 300 (M+, 57). Anal. calcd. for C15H12N2O3S: C, 59.99; H, 4.03; N, 9.33. Found: C, 59.94; H, 4.01; N, 9.36%. 2.2.4. Synthesis of ethyl 2‐((chloromethyl)thio)‐6‐cyano‐7‐ (4‐methoxphenyl)‐5‐oxo‐3,5‐dihydro‐[1,2,4]triazolo[1,5‐a] pyridine‐8‐carboxylate (12) Prepared according to procedure, to a solution of compound 1 (20 mmol) in THF 50 (mL) containing catalytic amount of NaH was added CH2Cl2 (23 mmol) and the reaction mixture was refluxed for 6 h. The solvent was removed under reduced pressure and the reaction mixture was poured on crushed ice containing AcOH and the precipitate was filtered off and washed was cold water several times and dried (Scheme 3). Recrystallized from DMF. Color: Brown. Yield: 43%. M.p.: 225‐227 C. FT‐IR (KBr, , cm‐1): 3362 (NH), 3118 (CH), 2908 (CH) 2116 (CN), 1688 (C=O), 1661 (C=O), 1630 (C=N); 1581 (C=C). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.16 (t, 3H, CH3), 3.74 (s, 3H, OCH3), 4.08 (q, 2H, CH2), 4.89 (s, 2H, SCH2), 8.64 (s, 1H, NH, D2O‐exchangeable), 6.62‐7.89 (m, 4H, Ar‐H). MS (EI, m/z (%)): 420 (M++2, 33), 418 (M+, 59.6). Anal. calcd. for C18H15N4O4SCl: C, 51.62; H, 3.61; N, 13.38. Found: C, 51.58; H, 3.59; N, 13.31%. 2.2.5. General procedure for synthesis of compounds 4a, 4b, 10 and 14 A solution of p‐toluene‐sulfonyl chloride (20 mmol) in pyridine (50 mL) was added dropwise to a solution of compound 3a and 13 (10 mmol) or a solution of p‐toluene‐ sulfonyl chloride (10 mmol) in pyridine (50 mL) was added drop‐wise to a solution of compound 3b and 9 (10 mmol) at 0 C, within 6 h. The mixture was stirred at room temperature and left overnight. It was then quenched with ice‐water containing HCl, and stirred for another 1 h. The precipitate obtained was filtered off and washed was methanol, cold water several times, dried and recrystallized from the appropriate solvent (Scheme 1‐3). Ethyl 2‐((1‐tosyl‐1H‐benzo[d]imidazol‐2‐yl)methylthio)‐6‐ cyano‐3,5‐dihydro‐7‐(4‐methoxyphenyl)‐5‐oxo‐3‐tosyl‐[1,2,4]‐ triazolo[1,5‐a]pyridine‐8‐carboxylate (4a): Recrystallized from DMF/H2O. Color: Pale brown. Yield: 46%. M.p.: 164 C. FT‐IR (KBr, , cm‐1): 1372 (O=S=O), 3116 (CH), 2898 (CH), 2214 (CN), 1676 (C=O), 1665 (C=O), 1630 (C=N); 1370 (O=S=O), 1580 (C=C). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.21 (t, 3H, CH3), 2.36 (brs, 6H, 2CH3), 3.73 (s, 3H, OCH3), 4.21 (q, 2H, CH2), 5.11 (s, 2H, SCH2), 6.84‐7.92 (m, 16H, Ar‐H). MS (EI, m/z (%)): 808 (M+, 37). Anal. calcd. for C39H32N6O8S3: C, 57.91; H, 3.99; N, 10.39. Found: C, 57.87; H, 3.96; N, 10.37%. 484 Motaal and Raslan / European Journal of Chemistry 5 (3) (2014) 481‐487 Scheme 3 Ethyl 2‐((benzo[d]oxazol‐2‐ylmethyl)thio)‐6‐cyano‐7‐(4‐ methoxyphenyl)‐5‐oxo‐3‐tosyl‐3,5‐dihydrol‐[1,2,4]‐triazolo[1,5‐ a]pyridine‐8‐carboxylate (4b): Recrystallized from DMF. Color: Brownish‐yellow. Yield: 39%. M.p.: 197 C. FT‐IR (KBr, , cm‐1): 3116 (CHarom.), 2891, 2850 (CH), 2216 (CN), 1681 (C=O), 1669 (C=O), 1635 (C=N); 1583 (C=C). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.19 (t, 3H, CH3), 2.34 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 4.19 (q, 2H, CH2), 5.22 (s, 2H, SCH2), 6.79‐7.85 (m, 12H, Ar‐H). MS (EI, m/z (%)): 655 (M+, 42). Anal. calcd. for C32H25N5O7S2: C, 58.62; H, 3.84; N, 10.68. Found: C, 58.58; H, 3.82; N, 10.67%. 3(2‐((1‐Tosyl‐1H‐benzo[d]imidazol‐2‐yl)methylthio)‐6‐ ethoxypyrimidin‐4‐yl)‐2H‐chromen‐2‐one (10): Recrystallized from dioxane/H2O. Color: Pale yellow crystals. Yield: 49%. M.p.: 168 C. FT‐IR (KBr, , cm‐1): 3118 (CH), 2893 (CH), 1694 (C=O), 1630 (C=N), 1180 (O=S=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.29 (t, 3H, CH3), 2.35 (s, 3H, CH3), 3.89 (q, 2H, CH2), 5.22 (s, 2H, SCH2), 6.83 (s, 1H, H‐5), 7.11‐7.96 (m, 12H, Ar‐H), 7.98 (s, 1H, H‐4chromen). MS (EI, m/z (%)): 584 (M+, 19). Anal. calcd. for C30H24N4O5S2: C, 61.63; H, 4.14; N, 9.58. Found: C, 61.59; H, 4.11; N, 9.55%. Ethyl 2‐(((8‐(ethoxycarbonyl)‐6‐cyano‐3,5‐dihydro‐7‐(4‐ methoxyphenyl)‐5‐oxo‐3‐tosyl‐[1,2,4]‐triazolo[1,5‐a]pyridine‐2‐ ylthio)methyl)sulfanyl)‐6‐cyano‐3,5‐dihydro‐7‐(4‐methoxy phenyl)‐5‐oxo‐3‐tosyl‐[1,2,4]triazolo[1,5‐a]pyridine‐8‐carboxy late (14): Recrystallized from DMF/H2O. Color: Brown. Yield: 65%. M.p.: 149‐151 C. FT‐IR (KBr, , cm‐1): 3119 (CH), 2855 (CH), 2218 (CN), 1683 (C=O), 1663 (C=O), 1630 (C=N); 1377 (O=S=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.24 (t, 6H, 2CH3), 2.36 (s, 6H, 2CH3), 4.18 (q, 4H, 2CH2), 3.75 (s, 6H, 2OCH3), 4.68 (s, 2H, SCH2), 7.15‐7.89 (m, 16H, Ar‐H). Anal. calcd. for C49H40N8O12S4: C, 55.46; H, 3.80; N, 10.56. Found: C, 55.40; H, 3.79; N, 10.53%. 2.2.6. General procedure for synthesis of compound 5a, 5b, and 11 Prepared according to procedure [53], to a solution of compound 4a, 4b, 10 and 14 (20 mmol) in CH2Cl2 (50 mL), H2O2 (30% w:v, 0.3 mL, 20 mmol in case of compound 4a, 4b, 9 and (0.6 mL), (40 mmol) in case of compound 14) in AcOH (10 mL) was added dropwise. The reaction mixture was heated at 80 C under stirring for 3‐6 h. The solvent was then evaporated under reduced pressure. The residue was poured in methanol ice cold water. The precipitate obtained was filtered off and washed with cold water several times, dried and recrystallized from the appropriate solvent (Scheme 1 and 2). 2‐((1‐Tosyl‐1H‐benzo[d]imidazol‐2‐yl)methylsulfinyl)‐6‐ cyano‐3,5‐dihydro‐7‐(4‐methoxyphenyl)‐5‐oxo‐3‐tosyl‐[1,2,4] triazolo[1,5‐a]pyridine‐8‐yl propionate (5a): Recrystallized from DMF. Color: Brown. Yield: 33%. M.p.: 247‐249 C. FT‐IR (KBr, , cm‐1): 3114 (CH), 2890 (CH), 2209 (CN), 1676 (C=O), 1661 (C=O), 1633 (C=N); 1583 (C=C). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.26 (t, 3H, CH3), 2.34‐2.36 (brs, 6H, 2CH3), 3.75 (s, 3H, OCH3), 4.23 (q, 2H, CH2), 5.40 (s, 2H, SCH2), 6.72‐7.81 (m, 16H, Ar‐H). MS (EI, m/z (%)): 824 (M+, 8). Anal. calcd. for C39H32N6O9S3: C, 56.78; H, 3.91; N, 10.19. Found: C, 56.71; H, 3.89; N, 10.17%. 2‐((Benzo[d]oxazol‐2‐yl)methylsulfinyl)‐6‐cyano‐3,5‐dihyd ro‐7‐(4‐methoxyphenyl)‐5‐oxo‐3‐tosyl‐[1,2,4]‐triazolo[1,5‐a] pyridine‐8‐yl propionate (5b): Recrystallized from DMF. Color: Pale brown. Yield: 43%. M.p.: 243‐244 C. FT‐IR (KBr, , cm‐1): 3119 (CH), 2895, 2857 (CH) 2213 (CN), 1679 (C=O), 1668 (C=O), 1631 (C=N); 1585 (C=C). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.24 (t, 3H, CH3), 2.35 (s, 3H, 2CH3), 3.73 (s, 3H, OCH3), 4.21 (q, 2H, CH2), 5.42 (s, 2H, SCH2), 6.72‐7.81 (m, 12H, Ar‐H). MS (EI, m/z (%)): 671 (M+, 16). Anal. calcd. for C32H25N5O8S2: C, 57.22; H, 3.75; N, 10.43. Found: C, 57.16; H, 3.74; N, 10.41%. 3‐(2‐((1‐Tosyl‐1H‐benzo[d]imidazol‐2‐yl)methylsulfinyl)‐6‐ ethoxypyrimidin‐4‐yl)‐2H‐chromen‐2‐one (11): Recrystallized from DMF/EtOH. Color: Dark brown. Yield: 38%. M.p.: 205‐206 C. FT‐IR (KBr, , cm‐1): 3145 (CH), 2894 (CH), 1694 (C=O), 1634 (C=N), 1583 (C=C). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.3 (t, 3H, CH3), 2.35 (s, 3H, CH3), 3.98 (q, 2H, CH2), 5.55 (s, 2H, SCH2), 6.82 (s, 1H, H‐5), 7.13‐7.93 (m, 12H, Ar‐H), 8.03 (s, 1H, H‐4chromen). MS (EI, m/z (%)): 600 (M+, 11). Anal. calcd. for C30H24N4O6S2: C, 59.99; H, 4.03; N, 9.33. Found: C, 59.92; H, 4.0; N, 9.29%. 2.3. Biological activity 2.3.1. Tested organisms Eight organisms are used as test organisms comprising of five bacteria (Staphylococcus aureus, Bacillus sp., Salmonella typhi, Escherichia coli [54,55], and Nisseria lactmica [56]) were obtained from Microbiology Laboratory of Faculty of Science, Qena and three fungi (Alternaria alternata strain HM01 [57], Aspergillus terreus strain HM13 [58], Fusarium nivale strain Motaal and Raslan / European Journal of Chemistry 5 (3) (2014) 481‐487 485 HM25) were obtained from Mycology Laboratory of Faculty of Science, Aswan .The cultures of bacteria and fungi were sub‐ cultured on Muller‐Hinton agar and C'zapek's‐agar slants respectively and stored at 4 C until required for study. 2.3.2. Antibacterial test using paper disc technique The tested compounds (1 mg/disc) on sterile filter paper discs (0.3 mm diameter) and dried at 40 C for 30 minutes. The prepared Muller‐Hinton agar plates were on cultured with each of test bacteria 107 CFU/mL, and the filter paper discs were placed on each plate. The plates were incubated at 37 C for 24 h. The zones of inhibition were measured and recorded. 2.3.3. Antifungal test using fungal growth rate technique This activity was carried out using C’zapekes agar medium in petri dishes and mixed with each compound by a final concentration (1 mg/plate) and then inoculated in central zone with a fresh culture fungal disc of 3 mm in diameter. All plates were incubated at 28 C. The diameters of cultures were measured in control dishes and in the treated plates containing culture medium supplemented with variable compounds and the average growth rates was measured. 3. Results and discussion 3.1. Synthesis 1,2,4‐Triazolo[1,5‐a]pyridine derivative (3a) were synthe‐ sized by stirring of ethyl 6‐cyano‐7‐(4‐methoxyphenyl)‐5‐oxo‐ 2‐thioxo‐1,2,3,5‐tetrahydro[1,2,4]triazolo[1,5‐a]pyridine‐8‐ carboxylate (1) with 2‐(chloromethyl)benzimidazole (2a) in sodium methoxide. The structure of the product 3a was assigned as ethyl 2‐((1H‐benzo[d]imidazol‐2‐yl)methylthio)‐6‐ cyano‐3,5‐dihydro‐7‐(4‐methoxyphenyl)‐5‐oxo‐[1,2,4]triazolo‐ [1,5‐a]pyridine‐8‐carboxylate based on the elemental analysis and spectral data which in agreement with this structure. Its IR spectrum indicate the absence of a free –SH absorption band and the appearance of absorption bands at 3375, 3268 cm‐1 assignable to 2NH, 3115 cm‐1 to CH, 2212 cm‐1 to CN, 1685, 1664 cm‐1 to CO, and 1586 cm‐1 to C=C functions. Its 1H NMR spectrum revealed the presence of three singlet signals at  11.43 ppm,  8.64 ppm,  4.64 ppm assignable to the NHimidazole, NHtriazole, and SCH2, respectively. The mass spectrum of compound 3a showed the molecular ion at m/z 500 (M+). Furthermore, the 13C NMR spectrum also revealed signal at 33.4 ppm due to SCH2 (Scheme 1). Similarly, 2‐(chloromethyl)benzooxazole (2b) reacted with compound 1 under the same conditions to yield compound 3b. The structure of the product 3b was assigned as ethyl 2‐ ((benzo[d]oxazol‐2‐yl)methylthio)‐6‐cyano‐3,5‐dihydro‐7‐(4‐ methoxyphenyl)‐5‐oxo‐[1,2,4]triazolo[1,5‐a]pyridine‐8‐ carboxylate based on the elemental analysis and spectral data which in agreement with this structure (see Experimental section). Reaction of compound 3a with tosyl chloride in pyridine gave the corresponding ethyl 2‐((1‐tosyl‐1H‐benzo[d]imidazol‐ 2‐yl)methylthio)‐6‐cyano‐3,5‐dihydro‐7‐(4‐methoxyphenyl)‐5‐ oxo‐3‐tosyl‐[1,2,4]‐triazolo[1,5‐a]pyridine‐8‐carboxylate, 4a. Its IR spectrum indicate the absence of a free 2NH absorption bands and the appearance of absorption bands at 1372 cm‐1 assignable to SO2, 2214 cm‐1 to CN, and 1676, 1655 cm‐1 to CO functions. Its 1H NMR spectrum revealed the presence of singlet signal at  5.11 ppm assignable to SCH2 (Scheme 1). Similarly, reaction of compound 3b with tosyl chloride in pyridine gave the corresponding 4b. The structure of the product 4b was assigned as ethyl 2‐((benzo[d]oxazol‐2‐ ylmethyl)thio)‐6‐cyano‐7‐(4‐methoxyphenyl)‐5‐oxo‐3‐tosyl‐ 3,5‐dihydrol‐[1,2,4]‐triazolo[1,5‐a]pyri‐dine‐8‐carboxylate based on the elemental analysis and spectral data which in agreement with this structure (see Experimental section). 2‐((1‐Tosyl‐1H‐benzo[d]imidazol‐2‐yl)methylsulfinyl)‐6‐ cyano‐3,5‐dihydro‐7‐(4‐methoxyphenyl)‐5‐oxo‐3‐tosyl‐[1,2,4]‐ triazolo[1,5‐a]pyridine‐8‐yl propionate (5a) was synthesized by refluxing with stirring a solution of compound 4a in dichloromethane and hydrogen peroxide in acetic acid. Its IR spectrum showed absorption bands at 2209 cm‐1 assignable to CN and 1676, 1661 cm‐1 to CO functions. Its 1H NMR spectrum revealed the presence of singlet signal at  5.4 ppm assignable to ‐SCH2. The mass spectrum of compound 5a showed the molecular ion at m/z 824 (M+) (Scheme 1). Similarly, refluxing with stirring compound 4b in dichloromethane and hydrogen peroxide in acetic acid yield the corresponding compound 5b. The structure of compound 5b was assigned as 2‐((benzo[d]oxazol‐2‐yl)methylsulfinyl)‐6‐ cyano‐3,5‐dihydro‐7‐(4‐methoxyphenyl)‐5‐oxo‐3‐tosyl‐[1,2,4]‐ triazolo[1,5‐a]pyridine‐8‐yl propionate based on the elemental analysis and spectral data which in agreement with this structure (see Experimental section). In continuation of our interest with the synthesis of fused hetero compounds [36], reaction of 3‐acetyl‐2H‐chromen‐3‐ one (6) with CS2 in the presence of NaH followed by methylation with CH3I to afford 3‐(3,3‐bis(methylthio) acryloyl)‐2H‐chromen‐2‐one, 7. The 1H NMR spectrum of the latter exhibited two characteristic singlet signals at  8.43 and 6.21 ppm for coumarine H‐4 and =CH proton, respectively. The mass spectrum of compound 7 showed the molecular ion peak at m/z 293 (M++1) corresponding to the molecular formula (C14H12O3S2). Reaction of compound 7 with thiourea in sodium ethoxide afforded the pyrimidine derivative, 8. The 1H NMR spectrum exhibited a broad signal at at  8.65 ppm for SH proton of pyrimidine and singlet signal for pyrimidine H‐5 at  6.81 ppm. The mass spectrum of compound 8 showed the molecular ion peak at m/z 300 corresponding to the molecular formula (C15H12N2O3S). Chromen‐2‐one derivative 9 was synthesized by stirring of 3‐(6‐ethoxy‐2‐marcaptopyrimidin‐4‐yl)‐2H‐chromen‐2‐one (8) with compound 2a in sodium methoxide (Scheme 2). The structure of the product 9 was assigned as 3‐(2‐((1H‐benzo [d]imidazol‐2‐yl)methylthio)‐6‐ethoxypyrimidin‐4‐yl)‐2H‐chro men‐2‐one based on the elemental analysis and spectral data which in agreement with this structure. Its IR spectrum indicate the absence of a free –SH absorption band and the appearance of absorption bands at 3279 cm‐1 assignable to NH, 3119 cm‐1 to CH and 1691 cm‐1 to COchromen functions. Its 1H NMR spectrum revealed the presence of two singlet signals at  11.13 and 4.39 ppm assignable to the NH and SCH2, respectively. The mass spectrum of compound 9 showed the molecular ion at m/z 430 (M+). Reaction of compound 9 with tosyl chloride in pyridine gave the corresponding 3(2‐((1‐tosyl‐1H‐benzo[d]imidazol‐2‐ yl)methylthio)‐6‐ethoxypyrimidin‐4‐yl)‐2H‐chromen‐2‐one, 10. The structure of the compound 10 was assigned based on the elemental analysis and spectral data. Its IR spectrum indicate the absence of a free NH absorption band of the benzimidazole and the appearance of absorption bands at 1180 cm‐1 assignable to SO2 and 1694 cm‐1 to CO functions. Its 1H NMR spectrum revealed the presence of two singlet signals at  2.35 ppm, and 5.22 ppm assignable to the methyl of tosyl and SCH2 protons, whereas the aromatic protons appeared as multiplets and doublet signals at  7.11‐7.96 ppm. The mass spectrum of compound 10 showed the molecular ion at m/z 584 (M+) (Scheme 2). 3‐(2‐((1‐Tosyl‐1H‐benzo[d]imidazol‐2‐yl)methylsulfinyl)‐ 6‐ethoxypyrimidin‐4‐yl)‐2H‐chromen‐2‐one (11) was synthe‐ sized by refluxing with stirring a solution of compound 10 in dichloromethane and hydrogen peroxide in acetic acid. The IR spectrum of compound 11 showed absorption bands at 3145 cm‐1 assignable to CH and 1694 cm‐1 to CO function. 486 Motaal and Raslan / European Journal of Chemistry 5 (3) (2014) 481‐487 Table 1. The antibacterial activity of compounds (1 mg/disc) *. Compound no Staphylococcus aureus Gram (+) Bacillus sp. Gram (+) Escherichia coli Gram (+) Neisseria Lactamica Gram (+) Salmonella Typhi Gram (‐) 3a + ‐ ‐ ‐ ‐ 3b ‐ ‐ + ‐ ‐ 4a + ‐ + ‐ ‐ 9 + + + + + 13 + ‐ + + + 5a ‐ ‐ ‐ ‐ ‐ 5b ‐ ‐ + ‐ ‐ 10 + + + + + 14 + + + + + 4b ‐ ‐ + ‐ ‐ 11 + ‐ ‐ + + * “+” = active; “‐“ = non‐active. Table 2. Effect of the compounds (1 mg/plate) on fungal growth rate. Compounds Altermaria altermata Aspergillus terreus Fusarium nivale 3a 2.30 1.3 3.7 3b 3.05 1.2 3.0 4a 2.20 1.5 3.1 9 2.60 1.1 2.9 13 2.60 0.9 3.9 5a 3.40 1.3 3.8 5b 2.50 1.2 4.2 10 2.25 1.2 3.1 14 2.60 1.1 3.7 4b 2.60 1.3 4.0 11 2.60 1.1 3.1 Its 1H NMR spectrum revealed the presence of singlet signal at  2.35 and 5.55 ppm assignable to methyl of tosyl and ‐CH2S, whereas the aromatic protons appeared as multiplets signals at  7.13‐7.93 ppm. The mass spectrum of compound 11 showed the molecular ion at m/z 600 (M+) (Scheme 2). 1,2,4‐Triazolo[1,5‐a]pyridine‐8‐carboxylate derivative 12 was synthesized by refluxing of compound 1 with dichloro methane in a solution of THF containing sodium hydride as a basic catalyst (Scheme 3). The structure of the product 12 was assigned as ethyl 2‐((chloromethyl)thio)‐6‐cyano‐7‐(4‐methox phenyl)‐5‐oxo‐3,5‐dihydro‐[1,2,4]triazolo[1,5‐a]pyridine‐8‐ carboxylate based on the elemental analysis and spectral data which in agreement with this structure. Its IR spectrum indicate the absence of a free –SH absorption band and the appearance of absorption bands at 3362 cm‐1 assignable to NH, 3118 cm‐1 to CH, 2116 cm‐1 to CN, and 1688, 1661 cm‐1 to CO functions. Its 1H NMR spectrum revealed the presence of three singlet signals at  8.64 and 4.89 ppm, assignable to the NHtriazole, and SCH2, respectively. The mass spectrum of compound 12 showed the molecular ion at m/z 420 (M+2, 33), 418 (M+, 59.6). Reaction of compound 12 with compound 1 in sodium methoxide with stirring afforded 1,2,4‐triazolo[1,5‐a]pyridine‐ 8‐carboxylate derivative 13 (Scheme 3). The structure of the product 13 was assigned as ethyl 2‐(((8‐(ethoxycarbonyl)‐6‐ cyano‐3,5‐dihydro‐7‐(4‐methoxyphenyl)‐5‐oxo‐[1,2,4]triazolo [1,5‐a]pyridine‐2‐ylthio)methyl)sulfanyl)‐6‐cyano‐3,5‐dihydro‐ 7‐(4‐methoxyphenyl)‐5‐oxo‐[1,2,4]triazolo[1,5‐a]pyridine‐8‐ carboxylate based on the elemental analysis and spectral data which in agreement with this structure. Its IR spectrum indicate the appearance of absorption bands at 3275 cm‐1 assignable to NH, 3119 cm‐1 to CH, 2215 cm‐1 to CN, and 1689, 1669 cm‐1 to CO functions. Its 1H NMR spectrum revealed the presence of a broad singlet signal at  8.78 ppm assignable to NHtriazole and singlet signal at  4.61 ppm to ‐SCH2S‐. Reaction of compound 13 with tosyl chloride in pyridine gave the corresponding ethyl 2‐(((8‐(ethoxycarbonyl)‐6‐cyano‐ 3,5‐dihydro‐7‐(4‐methoxyphenyl)‐5‐oxo‐3‐tosyl‐[1,2,4]triazolo [1,5‐a]pyridine‐2‐ylthio)methyl)sulfanyl)‐6‐cyano‐3,5‐dihydro‐ 7‐(4‐methoxyphenyl)‐5‐oxo‐3‐tosyl‐[1,2,4]triazolo[1,5‐a]pyridi ne‐8‐carboxylate, 14. Its IR spectrum indicate the absence of a free NH absorption bands and the appearance of absorption bands at 1377 cm‐1 assignable to SO2, 2218 cm‐1 to CN, and 1683, 1663 cm‐1 to CO. Its 1H NMR spectrum revealed the presence of singlet signals at  2.36 ppm assignable to the methyl protons of tosyl, and  4.68 ppm to ‐SCH2S‐ whereas the aromatic protons appeared as multiplets signals at  7.15‐7.89 ppm (Scheme 3). 3.2. Antimicrobial studies Only 1 mg of each compound was used to check its biological activity against bacteria (Table 1) and fungi (Table 2). The studied compounds showed biological activity with most of the tested bacteria and fungi. Compounds 9, 10 and 14 inhibited the growth of all testes bacteria while 5a had no activity to any studied bacterial species. The remaining compounds activity recorded less toxicity to the tested bacterial cell. These compounds almost inhibited all the studied fungi but Aspergillus terreus was slightly resistance. Compounds 9, 10, and 14 showed inhibition zones with all studied bacteria while compound 13 inhibit four bacterial species (S. aureus, S. typhi, E. coli and N. lactamica). However 11 could inhibit S. aureus, S. typhi, and N. lactamica). The compound 4a showed less activity against studied bacteria which could inhibit only two species (S. aureus and E. coli). Compounds 3a, 3b, 5b and 4b recorded the lowest inhibition activity where the first one inhibits S. aureus and the last three compounds inhibit only E. coli. No biological activity was recorded with compound 5a. The toxicity of most compounds on fungal cells was slightly different from bacterial cells. Therefore, Alternaria alternata growth rate in control culture was (4.15 cm). This growth decreased to almost half with compound 4a, 10 and 3a (2.20, 2.25 and 2.3 cm), respectively. The toxicity effect slightly decrease with compounds 5b (2.5 cm) and 9, 13, 14, 4b, and 11 (2.6 cm) while with compounds 3b and 5a was 3.05 and 3.40 cm, respectively (Table 2). In case of Aspergillus terreus (Table 2) its growth in control culture was 1.5 cm which similar to the growth with compound 4a (not toxic compound), whereas, slightly inhibition of the fungal growth was recorded with compound 3a, 5a, 4b (1.3 cm), 3b, 5b, and 10 (1.2 cm). This toxicity slightly increased with compound 9, 14, 11 (1.1 cm), and 13 (0.9 cm). Fusarium nivale was also sensitive to all compounds. Whereas control growth rate was 5 cm. Compounds 9 and 3b Motaal and Raslan / European Journal of Chemistry 5 (3) (2014) 481‐487 487 could inhibited the growth to 2.9 cm and 3.0 cm, respectively, while compound 4a, 10 and 11 reduced the growth rate to 3.1 cm. The remaining compounds’ toxicity on this fungal species decreased to 3.7 cm with compounds 3a and 14, 3.8 cm with 5a, 3.9 cm with 13, 4.0 cm with 4b, and 4.2 cm with 5b. 4. Conclusions In the present work, several new substituted sulfonamides and sulfinyl compound derivatives were obtained by the reaction of 2‐thioxo‐1,2,4‐triazolo[1,5‐a]pyridine and pyrimi dinethiol derivatives with (2‐chloromethyl)benzimidazole and/or (2‐chloromethyl)benzooxazole. A little amount (1 mg) of compounds 9, 10 and 14 was enough to inhibit the growth of all testes bacteria while compound 5a had no activity to any studied bacterial species. The remaining compounds activity recorded less toxicity to the tested bacterial cell. The tested compounds almost inhibited all the studied fungi but Aspergillus terreus was slightly resistance. Acknowledgement Authors are thankful to Aswan Faculty of Science, Aswan University, Egypt for facilities. References [1]. Lu, X.; Zhang, H.; Chen, G.; Luo, Y.; Ruan, B. F.; Chen, X. W.; Zhu, H. L.; Zhu, H. L. Bioorg. Med. Chem. 2011, 19, 6827‐6832. [2]. Luo, Y.; Qiu, K. M.; Lu, X.; Liu, K.; Fu, J.; Zhu, H. L. Bioorg. Med. Chem. 2011, 19, 4730‐4738. [3]. Chandak, N.; Bhardwaj, J. K.; Sharma, R. K.; Sharma, P. K. Eur. J. Med. Chem. 2013, 59, 203‐208. [4]. Kamal, A.; Swapna, P.; Shetti, R. V.; Shaik, A. B.; Narasimha Rao, M. P.; Gupta, S. Eur. J. Med. Chem. 2013, 62, 661‐669. [5]. Akurathi, V.; Dubois, L.; Lieuwes, N. G.; Chitneni, S. K.; Cleynhens, B. J.; Vullo, D.; Supuran, C. T.; Verbruggen, A. M.; Lambin, P.; Bormans, G. M. Nucl. Med. Biol. 2010, 37, 557‐564. [6]. Andrighetti‐Frohner, C. R.; De Oliveira, K. N.; Gaspar‐Silva, D.; Pacheco, L. K.; Joussef, A. C.; Steindel, M.; Simoes, C. M. O.; De Souza, A. M. T.; Magalhaes, U. O.; Afonso, I. F.; Rodrigues, C. R.; Nunes, R. J.; Castro, H. C. Eur. J. Med. Chem. 2009, 44, 755‐763. [7]. Gadad, A. K.; Mahajanshetti, C. S.; Nimbalkar, S.; Raichurkar, A. Eur. J. Med. Chem. 2000, 35, 853‐857. [8]. Azab, M.; Youssef, M.; El‐Bordany, E. Molecules 2013, 18, 832‐844. [9]. Ezabadi, I. R.; Camoutsis, C.; Zoumpoulakis, P.; Geronikaki, A.; Sokovic, M.; Glamocilija, J.; Ciric, A. Bioorg. Med. Chem. 2008, 16, 1150‐1161. [10]. Ghorab, M. M.; Ragab, F. A.; Heiba, H. I.; Arafa, R. K.; El‐Hossary, E. M. Eur. J. Med. Chem. 2010, 45, 3677‐3684. [11]. Ghorab, M. M.; Ragab, F. A.; Hamed, M. M. Eur. J. Med. Chem. 2009, 44, 4211‐4217. [12]. Bano, S.; Javed, K.; Ahmad, S.; Rathish, I. G.; Singh, S.; Alam, M. S. Eur. J. Med. Chem. 2011, 46, 5763‐5768. [13]. Sondhi, S. M.; Johar, M.; Singhal, N.; Dastidar, S. G.; Raghubir, R. Monatsh. Chem. 2000, 131, 511‐520. [14]. El‐Araby, M.; Omar, A.; Hassanein, H. H.; El‐Helby, A. G. H.; Abdel‐ Rahman, A. A. Molecules 2012, 17, 12262‐12275. [15]. Nanthakumar, R.; Muthurmani, P.; Girija, K. Arab. J. Chem. 2011, doi: 10.1016/j.arabjc.2010.12.035. [16]. Al‐Mohammed, N. N.; Alias, Y.; Abdullah, Z.; Shakir, R. M.; M. Taha, E. M.; Hamid, A. A. Molecules 2013, 18, 11978‐11995. [17]. El‐masry, A. H.; Fahmy, H. H.; Abdelwahed, S. H. A. Molecules 2000, 5, 1429‐1438. [18]. Khalil, M. A. A. J. Heterocycl. Chem. 2012, 49, 806‐813. [19]. Alen, J.; Robeyns, K.; De Borggraeve, W. M. Tetrahedron 2008, 64, 8128‐8133. [20]. Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Change, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235‐2246. [21]. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893‐ 930. [22]. Siddiqui, N.; Alam, M. S. Der Pharm. Chem. 2010, 2, 163‐171. [23]. Kamder, G. C.; Bhatt, D. J.; Parith, A. R. J. Indian Chem. Soc. 1988, 65, 67‐68. [24]. Pereira, E. R.; Sancelme, M.; Voldoire, A.; Prudhomme, M. Bioorg. Med. Chem. Lett. 1997, 7, 2503‐2507. [25]. Viti, G.; Namnicine, R.; Ricci, R.; Pestelline, V.; Abeli, L.; Funo, M. Eur. J. Med. Chem. 1994, 29, 401‐406. [26]. Abd El Aziz, H. A.; Gomha, S. M. Int. J. Pharm. Pharm. Sci. 2013, 5, 183‐ 189. [27]. Al‐Issa, S. A. Molecules 2012, 17, 10902‐10915. [28]. Chandrashekhar, C. H.; Latha, K. P.; Vagdevi, H. M.; Vaidya, V. P.; Vijaya Kumar, M. L. Der Chem. Sinica 2013, 4, 75‐78. [29]. Fotouhi, L.; Hekmatshoar, R.; Heravi, M. M.; Sadjadi, S.; Rasmi, V. Tetrahedron Lett. 2008, 49, 6628‐6632. [30]. Bekircan, O.; Bektas, H. Molecules 2006, 11, 469‐477. [31]. El‐Sherief, H. A. H.; Hozien, Z. A.; El‐Mahdy, A. F. M.; Sarhan, A. A. O. Arkivoc 2011, 10, 71‐84. [32]. Mahmoud, M. R.; El‐Shahawi, M. M.; Abu El‐Azm, F. S. M.; Farahat, S. E. Amer. J. Org. Chem. 2011, 1, 14‐20. [33]. Singh, T.; Sreenivas, S.; Parameshwar, R.; Abhimanyu, R.; Indira, K.; Vyashnavi, V.; Lavanya, CH.; Srinivas, M. Int. J. Bioassays. 2012, 2, 256‐ 259. [34]. Fadda, A. A.; Abdel‐Rahman, A. A. H.; Hamed, E. A.; Khalil, E. H. Amer. J. Org. Chem. 2012, 2, 7‐13. [35]. Barsy, M. A.; El‐Rady, E. A.; Ismael, M. A. J. Heterocycl. Chem. 2012, 49, 388‐393. [36]. Khalil, M. A.; Sayed, S. M.; Raslan, M. A. J. Korean Chem. Soc. 2013, 57, 612‐617. [37]. Singh, I.; Kaur, H.; Kumar, S.; Kumar, A.; Lata, S.; Kumar, A. Int. J. Chem. Tech. Res. 2010, 2, 1745‐1752. [38]. Khafagy, M. M.; Abd El‐Wahab, A. H. F.; Eid, F. E.; El‐Agrody, A. M. Il Farmaco 2002, 57, 715‐722. [39]. Sayed, S. M.; Khalil, M. A.; Raslan, M. A. Amer. J. Org. Chem. 2012, 2, 151‐160. [40]. Khalil, M. A.; Sayed, S. M.; Raslan, M. A. Amer. J. Org. Chem. 2012, 2, 161‐170. [41]. Khalil, M. A.; Sayed, S. M.; Raslan, M. A. Amer. J. Org. Chem. 2012, 2, 171‐181. [42]. Sayed, S. M.; Raslan, M. A.; Khalil, M. A.; Dawood, K. M. Heteroatom Chem. 1999, 10, 385‐390. [43]. Raslan, M. A.; Sayed, S. M.; Khalil, M. A.; Farag, A. M. Heteroatom Chem. 2000, 11, 94‐101. [44]. Sayed, S. M.; Selim, M. A.; Raslan, M. A.; Khalil, M. A. Heteroatom Chem. 2000, 11, 362‐369. [45]. Sayed, S. M.; Khalil, M. A.; Selim, M. A.; Raslan, M. A. Synth. Commun. 2002, 32, 481‐495. [46]. Dawood, K. M.; Raslan, M. A. J. Heterocycl. Chem. 2008, 45, 137‐141. [47]. Raslan, M.; Khalil, M.; Sayed, S. Heterocycles 2013, 87, 2567‐2576. [48]. El‐Kazak, A. M.; Ibrahim, M. A. Arkivoc 2013, 3, 282‐293. [49]. Gellis, A.; Boutatah, N.; Vanelle, P. Green Chem. 2006, 8, 483‐487. [50]. Kristinsson, H. Synthesis 1979, 102‐107. [51]. Morton, R.; Chang, H.; Craine, L.; Edwin, H. J. Org. Chem. 1985, 50, 2205‐2219. [52]. Chauhan, S. M. S.; Junjappa, H. Tetrahadron 1976, 32, 1779‐1787. [53]. Avinash, P.; Swastike, G.; Jogendra, H.; Santosh, T. Int. J. Pharm. Chem. 2012, 3, 89‐92. [54]. Vogt, R. L.; Dippold, L. Public Health Rep. 2005, 120, 174‐178. [55]. Hollis, D. G.; Wiggins, G. L.; Weaver, R. W. Appl. Microbiol. 1969, 17, 71‐77. [56]. Hudault, S.; Guignot, J.; Servin, A. L. Gut 2001, 49, 47‐55. [57]. Wiest, P.; Kurt, W.; Michael, R. J.; Anne, B. M.; Tom, I. A.; William, W.; Michael, M. L. Rev. Infect. Dis. 1987, 9, 799‐803. [58]. Shimada, A.; Kusano, M.; Takeuchi, S.; Fujioka, S.; Inokuchi, T.; Kimura, Y. J. Biosciences 2002, 57, 459‐464.