untitled ISSN 215 Synthes and fuse Yaser Abd 1 Organic Chemi 2 Organic Chemi 3 Organic Chemi 4 Pharmaceutica 5 Organic Chemi * Corresponding Tel.: +20.100.53 ARTICLE IN DOI: 10.5155/e Received: 22 No Received in rev Accepted: 06 Fe Published onlin Printed: 31 Mar KEYWORDS Bis‐quinazoline Triazolo‐quinaz 4‐Chloroquinaz Pyrimidino‐qui 4‐Hydrazinoqu 4‐Heteroarylqu 1. Introduct 2,4‐Disub spectrum of Such as, anti [8], kinases immune act receptors [14 For the a [15‐19] on th ting biologic derivatives w molecules as second chr biological an the reaction zoline (2) wi 2. Experime 2.1. Instrum 53‐2249 (Print) sis and ch ed triazol del‐Moemen istry Laboratory, Fa istry Department, F istry Department, F al Chemistry Depar istry Department, F g author at: Organi 338354. Fax: +20.02 FORMATION eurjchem.7.1.128‐1 ovember 2015 vised form: 18 Janu ebruary 2016 ne: 31 March 2016 rch 2016 S e zoline zolines inazoline inazoline uinazoline tion bstituted quina f biological an itumor agents inhibitors [9, tivators [13], a 4]. above findings he synthesis of cal activity. We with the aim o s well as gettin romophore w nd pharmaceuti s of 2‐[(E)‐2‐(f ith some nitrog ental mentation E / ISSN 2153‐225 htt Europ aracteriz lo quinazo n El‐Badry 1,2 Faculty of Specific E Faculty of Science, T Faculty of Women`s rtment, Ibn Sina Na Faculty of Science, A ic Chemistry Labor 23.3388032. E‐mai 134.1370 uary 2016 azoline derivati nd pharmaceut [6], anticancer 10], antimicro and modulator and in continua novel heterocy e synthesis var btaining a sour g quinazoline d which possess ical application furan‐2‐yl)ethe en and carbon uropean Journal Europ 57 (Online)  20 tp://dx.doi.org/ pean Jo Journal web ation of s oline deri 2,*, Ekhlass N Education, Ain Sham Taif University, Khu s for Arts, Science a ational College for M Ain Shams Universi ratory, Faculty of Sp l address: yasser_el ABSTRACT Treatment of and secondar aminoquinazo Hydrazinolysi hydrazine aff obtained via aldehydes. Ad compound 2 w quinazoline ( using interac cyclization. A spectral data Cite this: Eur. ives possess a tical activities [7], CD38 inhi obial agents [1 rs of adenosin ation of our pro yclic systems ex ieties of quina rce of function derivatives bea some inter ns. Herein, we r enyl]‐4‐chloro‐q nucleophiles. l of Chemistry 7 pean Journal of C 016 Atlanta Pub 10.5155/eurjche ournal bpage: www. ome new ivatives Nassar 3,4 an ms University, 1156 urma, 21985, Kingd and Education, Ain Medical Studies, 21 ity, 11566 Abbassey pecific Education, A lbadri@sedu.asu.ed chloroquinazoli ry amines (mo olines (3a,b an is of compound forded compoun a one‐pot react dditionally, 1,2,4 was treated with (13) has been c ction with ma All the synthesi like, FT‐IR, 1H N . J. Chem. 2016, broad [1‐5]. bitors 11,12], ne A3 ogram xhibit‐ zoline alized aring a esting report quina‐ use app silic spe and resp as use 1H Elem Dor 2.2. 2.2. qui (0.0 atm pre (1) (2016) 128‐ Chemistry lishing House LL em.7.1.128‐134. of Che .eurjchem.co w 4‐hetero nd Mahr Abd 66 Abbasseya, Cairo dom of Saudi Arabi Shams University, 1 1411, Jeddah, Kingd ya, Cairo, Egypt Ain Shams Universi du (Y.A. El‐Badry). ne (2) with prim rpholine, piper nd 4a,b), 4‐aryl d 2 using hydra nd 8 and 9a,b. 1 tion of chloroqu 4‐trizolo‐quinaz h acid hydrazide constructed via alononitrile foll ized compound MR, 13C NMR, an 7(1), 128‐134 All reagents a e by the usua paratus; uncorr ca gel 60F254 w ectra: FT‐IR Nic d 13C NMR s pectively; in CD internal standa ed where appro and 13C NMR mental analyse rtmund. . Synthesis .1. Synthesis of inazoline (2) [2 A mixture of qu 01 mole) in PO mosphere. The ssure and the r ‐134 LC ‐ All rights re .1370 emistry m oaryl quin del‐Aziz El‐H o, Egypt ia 11767, Cairo, Egyp dom of Saudi Arabia ty, 11566 Abbassey mary amines (2‐a ridine, and pipe l quinazolines azine hydrate, p 1,2,4‐Trizolo‐qui uinazoline (2), h zoline derivative es like acetyl and a three‐step co owed by part s were fully ch nd HR‐MS. nd solvents we al procedures. rected. TLC: M ith detection by colet Impact 40 spectra: Bruke DCl3 or DMSO‐d ard, J in Hz. D priate, to aid th spectra. HRMS s were carried f 2‐[(E)‐2‐(fura 20] uinazolinone (1 OCl3 (5 mL) wa excess POCl3 residue was pou served ‐ Printed y nazoline Hashash 5 pt a ya, Cairo, Egypt. aminothiazoles a erazine) furnish (5a,b), and bi phenyl hydrazin inazoline deriva hydrazine hydra es (10a,b) were d benzoyl hydra onversion of chl tial hydrolysis haracterized us ere dried and p M.p.: Büchi® Merck TLC alum y UV quenching 00D; KBr pellet er at 400 an d6; δ in ppm re DEPT135 NMR he assignment o S (FAB+): JEOL out at Technica an‐2‐yl)ethenyl 1) (2.38 g, 0.01 as refluxed for was distilled u ured on ice. d in the USA and sulpha drug hed 4‐substitute squinazoline (6 ne, and sulphon atives (7a‐c) we ate, and aromat e furnished whe azides. Pyrimidin loroquinazoline and hetero‐rin ing physical an purified before melting point minium sheets, g at 254 nm. IR ts; ν in cm‐1. 1H nd 100 MHz, elative to Me4Si R spectroscopy: of signals in the L JMS‐SX 102A. al University of l]‐4‐chloro‐ mole) and PCl5 r 2 h under Ar under reduced gs) ed 6). nyl re tic en no 2 ng nd e t , R H , i : e . f 5 r d El‐Badry et al. / European Journal of Chemistry 7 (1) (2016) 128‐134 129 Scheme 1 Scheme 2 The separated solid precipitated was filtered off, dried and crystallized from ethanol to afford chloroquinazoline 2 (Scheme 1). Color: Brown. Yield: 65%. M.p.: 269‐271 °C. 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 6.75 (s, 1H, Furyl‐H), 6.92 (d, J = 3.3Hz, 1H, Furyl‐H), 7.07 (d, J = 14.3 Hz, 1 H, =CH), 7.59 (t, J = 7.05 Hz, 2 H, Ar‐H), 7.94 (m, 3 H, =CH + 2 Ar‐H), 8.14 (d, J= 7.05 Hz, 1 H, furyl‐H). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 160.5 (C), 153.1 (C), 150.3 (C), 147.4 (C), 135.5 (CH), 130.3 (CH), 127.5 (CH), 126.4 (2CH), 122.5 (CH), 119.9 (C), 117.9 (CH), 113.5 (CH), 112.7 (CH). HRMS (EI, m/z) calcd. for C14H10ClN2O, 257.0493; found 257.0482. Anal. calcd. for C14H9ClN2O: C, 65.5; H, 3.5; N, 10.9. Found: C, 65.3; H, 3.6; N, 11.4%. 2.2.2. Synthesis of quinazolin‐4‐amines 3a,b A mixture of 4‐chloroquinazoline 2 (2.57 g, 0.01 mol) and 2‐aminothiazole and/or 2‐aminothiadiazole (0.01 mol) in dry pyridine (20 mL) was heated under reflux for 2 h. The reaction mixture after cooling was poured over HCl/crushed ice. The reaction mixture was concentrated, cooled and the solid obtained was filtered off and recrystallized from EtOH to give compound 3a and 3b, respectively (Scheme 2) 2‐[(E)‐2‐(furan‐2‐yl)ethenyl]‐N‐(1,3‐thiazol‐2‐yl)quinazolin‐ 4‐amine (3a): Color: Beige. Yield: 79%. M.p.: 194‐196 °C. FT‐IR (KBr, , cm‐1): 3164 (NH), 3059 (CH arom.), 2938 (CH aliph.), 1624 (C=N), 1162 (CS). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 6.49 (s, 1H, furyl‐H), 6.64 (d, J = 3.3 Hz, 1 H, furyl‐H), 6.79 (d, J = 14.8 Hz, 1 H, =CH), 6.91 (d, J = 3.1 Hz, 1 H, tiazole‐ H), 7.44‐7.52 (m, 4 H, =CH, thiazole‐H + 2 Ar‐H), 7.73‐7.78 (m, 2 H, Ar‐H), 8.16 (d, J = 8.3 Hz, 1 H, Ar‐H), 9.08 (brs, 1 H, NH). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 162.2 (C), 156.9 (C), 155.4 (C), 150.8 (C), 146.8 (CH), 142.9 (CH), 138.6 (CH), 135.5 (CH), 129.4 (CH), 127.7 (CH), 116.9 (C), 116.4 (C), 115.1 (CH), 114.3 (CH), 113.6 (CH), 112.7 (CH). HRMS (EI, m/z) calcd. for C17H12N4OS, 320.0732; found 320.0736. Anal. calcd. for C17H12N4OS: C, 63.73; H, 3.78; N, 17.49. Found: C, 63.86; H, 3.81; N, 17.34%. 2‐[(E)‐2‐(furan‐2‐yl)ethenyl]‐N‐(1, 3, 4‐thiadiazol‐2‐yl) quina‐ zolin‐4‐amine (3b): Color: Beige. Yield: 66%. M.p.: 213‐215 °C. FT‐IR (KBr, , cm‐1): 3159 (NH), 3061 (CH arom.), 1626 (C=N), 1158 (CS). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 6.53 (s, 1H, , furyl‐H), 6.63 (d, J = 3.3 Hz, 1 H, furyl‐H), 6.84 (d, J = 14.8 Hz, 1 H, =CH), 7.21 (t, J = 8.13 Hz, 1 H, Ar‐H), 7.39‐7.74 (m, 4 H, =CH, thiazole‐H + 2 Ar‐H), 8.13 (d, J = 8.13 Hz, 1 H, Ar‐H), 8.63 (s, 1 H, thiazole‐H), 9.06 (brs, 1 H, NH). HRMS (EI, m/z) calcd. for C16H11N5OS , 321.0784; found 321.0788. Anal. calcd. 130 El‐Badry et al. / European Journal of Chemistry 7 (1) (2016) 128‐134 for C16H11N5OS: C, 59.80; H, 3.45; N, 21.79. Found: C, 59.96; H, 3.59; N, 21.58%. 2.2.3. Synthesis of sulfonamides 4a,b A solution of compound 2 (0.01 mol) and sulfa drugs namely, sulfacetamide and/or sulfaguanidine (0.01 mol) in 1,4‐dioxane (20 mL) was refluxed for 5 h. The mixture was concentrated and the formed precipitate was washed with water, filtered off, and crystallized from the proper solvent to give compound 4a and 4b, respectively (Scheme 2). N‐[4‐({2‐[(E)‐2‐(furan‐2‐yl)ethenyl] quinazolin‐4‐yl} amino) benzene‐1‐sulfonyl]acetamide (4a): Color: Pale yellow. Yield: 83%. M.p.: 208‐210 °C (PhCH3). FT‐IR (KBr, , cm‐1): 3164, 3357 (NH), 3055 (CH arom.), 1598, 1628 (C=N), 1198 (SO2). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 2.07 (s, 3H, CH3), 6.51 (s, 1H, furyl‐H), 6.61‐6.72 (m, 2 H, furyl‐H + =CH), 7.28‐ 7.46 (m, 5 H, furyl‐H, =CH + 3 Ar‐H), 7.68‐7.77 (m, 4 H, Ar‐H), 8.13 (d, J = 8.13 Hz, 1 H, Ar‐H), 8.68 (s, 1 H, NH), 8.93 (s, 1 H, NH). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 168.5 (C), 162.3 (C), 154.3 (C), 153.4 (C), 147.9 (C), 144.7 (CH), 141.2 (CH), 139.5 (CH), 136.4 (CH), 131.7 (CH), 129.1 (CH), 127.3 (CH), 126.8 (C), 117.2 (C), 115.7 (CH), 114.3 (CH), 112.7 (CH), 112.3 (CH), 109.8 (CH), 24.3 (CH3). HRMS (EI, m/z) calcd. for C22H18N4O4S, 434.1049; found 434.1053. Anal. calcd. for C22H18N4O4S : C, 60.82; H, 4.18; N, 12.90. Found: C, 60.68; H, 4.23; N, 12.99%. N‐carbamimidoyl‐4‐({2‐[(E)‐2‐(furan‐2‐yl)ethenyl] quinazo lin‐4‐yl}amino)benzene‐1‐sulfonamide (4b): Color: Pale yellow. Yield: 74%. M.p.: 196‐198 °C (AcOH). FT‐IR (KBr, , cm‐1): 3189, 3368 (NH), 3058 (CH arom.), 1623 (C=N), 1179 (SO2). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 6.49 (s, 1H, furyl‐ H), 6.63 (d, J = 3.2 Hz, 1 H, furyl‐H), 6.69‐6.74 (m, 2 H, =CH + Ar‐H), 7.28 (t, J = 8.13 Hz, 1 H, Ar‐H), 7.42‐7.51 (m, 4 H, furyl‐H, =CH &+ 2 Ar‐H), 7.73‐7.79 (m, 4 H, Ar‐H), 8.16 (d, J = 8.13 Hz, 1 H, Ar‐H), 9.30 (s, 4 H, NH`s). HRMS (EI, m/z) calcd. for C21H19N6O3S , 435.1239; found 435.1243. Anal. calcd. for C21H18N6O3S : C, 58.05; H, 4.18; N, 19.34. Found: C, 58.32; H, 4.36; N, 19.12%. 2.2.4. Synthesis of quinazolines 5a,b A mixture of chloroquinazoline 2 (3.92 g, 0.01 mol) and morpholine and/or piperidine (0.01 mol) was heated at 140 °C for 5 min then 20 mL of ethanol was added and the reaction mixture was refluxed for 3 h. The excess solvent was distilled off and the solid that separated after cooling was collected and recrystallized from ethanol to give compound 5a and 5b, respectively (Scheme 2). 2‐[(E)‐2‐(furan‐2‐yl)ethenyl]‐4‐(morpholin‐4‐yl)quinazoline (5a): Color: Beige. Yield: 72%. M.p.: 293‐295 °C. FT‐IR (KBr, , cm‐1): 3055 (CH arom.), 2939 (CH aliph.), 1627 (C=N). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.42‐2.49 (m, 4H, 2CH2), 3.67‐ 3.74 (m, 4H, 2CH2), 6.52 (s, 1H, furyl‐H), 6.61‐6.69 (m, 3 H, furyl‐H, =CH + Ar‐H), 7.23 (t, J = 8.15 Hz, 1 H, Ar‐H), 7.46‐7.58 (m, 2 H, furyl‐H + =CH), 7.72‐7.81 (m, 2 H, Ar‐H). 13C NMR (100 MHz, CDCl3, δ, ppm): 159.3 (C), 155.6 (C), 152.5 (C), 147.8 (C), 145.9 (CH), 137.4 (CH), 129.1 (CH), 128.2 (CH), 127.7 (CH), 126.8 (CH), 115.9 (C), 112.6 (CH), 112.3 (CH), 108.9 (CH), 66.2 (2CH2), 49.7 (2CH2). HRMS (EI, m/z) calcd. for C18H17N3O2, 307.1321; found 307.1326. Anal. calcd. for C18H17N3O2: C, 70.34; H, 5.58; N, 13.67. Found: C, 70.61; H, 5.67; N, 13.48%. 2‐[(E)‐2‐(furan‐2‐yl)ethenyl]‐4‐(piperazin‐1‐yl)quinazoline (5b): Color: Pale yellow. Yield: 77%. M.p.: 302‐304 °C. FT‐IR (KBr, ν, cm‐1): 3186 (NH), 3062 (CH arom.), 2941 (CH aliph.), 1624 (C=N). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.51‐ 2.56 (m, 4H, 2CH2), 3.49‐3.54 (m, 4H, 2CH2), 6.55 (s, 1H, furyl‐ H), 6.61‐6.68 (m, 3 H, furyl‐H, =CH + Ar‐H), 7.16 (t, J = 8.13 Hz, 1 H, Ar‐H), 7.52‐7.67 (m, 4 H, furyl‐H, =CH + 2Ar‐H), 7.81 (d, J = 8.13 Hz, 1 H, Ar‐H). HRMS (EI, m/z) calcd. for C18H18N4O, 306.1481; found 306.1483. Anal. calcd. for C18H18N4O: C, 70.57; H, 5.92; N, 18.29. Found: C, 70.29; H, 5.80; N, 18.08%. 2.2.5. Synthesis 4,4'‐(piperazine‐1,4‐diyl)bis(2‐[(E)‐2‐ (furan‐2‐yl)ethenyl]quinazoline) (6) A mixture of chloroquinazoline 2 (3.92 g, 0.01 mol) and piperidine (1.73 g, 0.02 mol) was heated at 140 °C for 5 min then 20 mL of ethanol was added and the reaction mixture was refluxed for 3 h. The excess solvent was distilled off and the solid that separated after cooling was collected and recrystallized from ethanol to give compound 6 (Scheme 2). Color: Brown. Yield: 58%. M.p.: 230‐231 °C. FT‐IR (KBr, , cm‐ 1): 3056 (CH arom.), 2937 (CH aliph.), 1624 (C=N). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 3.58‐3.82 (m, 8 H, 4 CH2), 6.43 (s, 2 H, furyl‐H), 6.61‐6.88 (m, 8 H, 2 furyl‐H, 4 =CH + 2 Ar‐H), 7.22 (t, J = 8.11 Hz, 2 H, 2 Ar‐H), 7.52‐7.69 (m, 6 H, 2 furyl‐H + 4 Ar‐ H). HRMS (EI, m/z) calcd. for C32H26N6O2, 526.2117; found 526.2122. Anal. calcd. for C32H26N6O2: C, 72.99; H, 4.98; N, 15.96. Found: C, 73.27; H, 5.06; N, 16.17%. 2.2.6. Synthesis of triazolo quinazolines 7a‐c Procedure A: A mixture of compound 2 (2.57 g, 0.01 mol), hydrazine hydrate (0.75 g, 0.015 mol), and aromatic aldehydes namely, salicylaldehyde, 4‐methoxy benzaldehyde, and cinnamaldehyde in 20 mL of N,N‐dimethylformamide was refluxed for 4 h. The reaction mixture was concentrated, cooled and the residue was poured over cold water. The solid that formed was filtered off and crystallized from the suitable solvent to afford compound 7a‐c (Scheme 3). Procedure B: A mixture of 4‐hydrazinylquinazoline 8 (2.52 g, 0.01 mol) and aromatic aldehydes namely, salicylaldehyde, 4‐methoxy benzaldehyde, and cinnamaldehyde in glacial acetic acid (30 mL) was heated under reflux for 6 h. The excess solvent was distilled off and the residue was left overnight, then the solid that separated was collected, dried, and crystallized from the proper solvent to give compound 7a‐c (Scheme 3). 2‐{5‐[(E)‐2‐(furan‐2‐yl)ethenyl][1,2,4]triazolo[4, 3‐c] quina‐ zolin‐3‐yl}phenol (7a): Color: Pale yellow. Yield: 63%. M.p.: 232‐233 °C. FT‐IR (KBr, , cm‐1): 3448 (OH), 3058 (CH arom.), 1623 (C=N). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 5.24 (brs, 1H, OH), 6.49 (s, 1H, furyl‐H), 6.63‐6.79 (m, 3 H, furyl‐H, =CH + Ar‐H), 7.13‐7.26 (m, 3 H, Ar‐H), 7.51 (d, J = 3.4 Hz, 1 H, furyl‐H), 7.78 (d, J = 15.4 Hz, 1 H, =CH), 8.09‐8.18 (m, 4 H, Ar‐H). HRMS (EI, m/z) calcd. for C21H14N4O2, 354.1117; found 354.1121. Anal. calcd. for C21H14N4O2: C, 71.18; H, 3.98; N, 15.81. Found: C, 71.42; H, 4.17; N, 16.07%. 5‐[(E)‐2‐(furan‐2‐yl)ethenyl]‐3‐(4‐methoxyphenyl)[1, 2, 4] triazolo[4,3‐c]quinazoline (7b): Color: Beige. Yield: 67%. M.p.: 208‐209 °C (AcOH). FT‐IR (KBr, , cm‐1): 3054 (CH arom.), 2942 (CH aliph.), 1625 (C=N). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 3.81 (s, 3 H, CH3), 6.52 (s, 1 H, furyl‐H), 6.63‐6.82 (m, 4 H, furyl‐H, =CH, 2 Ar‐H), 7.21 (t, J = 8.39 Hz, 1 H, Ar‐H), 7.49‐ 7.66 (m, 2 H, furyl‐H + =CH), 8.09‐8.21 (m, 5 H, Ar‐H). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 159.4 (C), 154.7 (C), 151.3 (C), 149.3 (C), 146.2 (C), 139.5 (CH), 138.9 (C), 132.1 (CH), 128.6 (2CH), 127.1 (2CH), 125.9 (C), 124.2 (C), 118.6 (2CH), 117.8 (CH), 114.8 (CH), 112.0 (CH), 110.4 (CH), 109.1 (CH), 54.3 (CH3). HRMS (EI, m/z) calcd. for C22H17N4O2, 369.1352; found 369.1355. Anal. calcd. for C22H16N4O2: C, 71.73; H, 4.38; N, 15.21. Found: C, 71.97; H, 4.26; N, 15.43%. 5‐[(E)‐2‐(furan‐2‐yl)ethenyl]‐3‐[(E)‐2‐phenylethenyl][1,2, 4] triazolo[4,3‐c]quinazoline (7c): Color: Beige. Yield: 67%. M.p.: 208‐209 °C (AcOH). FT‐IR (KBr, , cm‐1): 3057 (CH arom.), 1624 (C=N). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 6.47 (s, 1H, furyl‐H), 6.61‐6.72 (m, 2 H, furyl‐H + =CH), 7.13 (t, J = 8.13 Hz, 1 H, Ar‐H), 7.21 (d, J = 15.4 Hz, 1 H, =CH‐Ar), 7.34‐7.46 (m, 7 H, furyl‐H, =CH‐Ar + 5 Ar‐H), 7.72 (d, J = 15.4 Hz, 1 H, =CH), El‐Badry et al. / European Journal of Chemistry 7 (1) (2016) 128‐134 131 Scheme 3 8.11‐8.17 (m, 3 H, Ar‐H). HRMS (EI, m/z) calcd. for C23H16N4O, 364.1324; found 364.1329. Anal. calcd. for C23H16N4O: C, 75.81; H, 4.43; N, 15.38. Found: C, 76.07; H, 4.29; N, 15.17%. 2.2.7. Synthesis of 2‐[(E)‐2‐(furan‐2‐yl)ethenyl]‐4‐ hydrazinylquinazoline (8) A solution of compound 2 (2.57 g, 0.01 mol) and hydrazine hydrate (0.75 g, 0.015 mol) in absolute ethanol (30 mL) in the presence of a few drops of piperidine was heated under reflux at 70 °C for 6 h. The excess solvent was distilled off under reduced pressure and the solid that obtained after cooling was collected and crystallized from EtOH/H2O to afford compound 8 (Scheme 3). Color: Beige. Yield: 81%. M.p.: 362‐363 °C. FT‐IR (KBr, , cm‐1): 3168, 3305 (NH), 3054 (CH arom.), 1628 (C=N). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 4.87 (brs, 3 H, NH`s), 6.53 (s, 1H, furyl‐H), 6.63‐6.70 (m, 2 H, furyl‐H + =CH), 7.12 (d, J = 15.6 Hz, 1 H, =CH), 7.42‐7.49 (m, 2 H, furyl‐H + Ar‐ H), 7.76‐7.89 (m, 3 H, Ar‐H). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 161.5 (C), 154.9 (C), 153.8 (C), 151.0 (C), 146.7 (CH), 139.2 (CH), 137.9 (CH), 126.9 (CH), 126.3 (CH), 121.8 (CH), 118.9 (C), 116.8 (CH), 113.3 (CH), 112.5 (CH). HRMS (EI, m/z) calcd. for C14H12N4O, 252.1011; found 252.1017. Anal. calcd. for C14H12N4O: C, 66.65; H, 4.79; N, 22.21. Found: C, 66.89; H, 4.63; N, 21.94%. 2.2.8. Synthesis of hydrazinyl quinazolines 9a,b An equimolar mixture of compound 2 (2.57 g, 0.01 mol) and phenyl hydrazine and/or sulphonyl hydrazine (0.01 mol) in N,N‐dimethylformamide (30 mL) was heated under reflux at 100 °C for 4 h. The reaction mixture after cooling was poured over cold water and the precipitate that separated was filtered off and crystallized from the proper solvent to afford compound 9a and 9b, respectively (Scheme 3). 2‐[(E)‐2‐(furan‐2‐yl)ethenyl]‐4‐(2‐phenylhydrazinyl) quina‐ zoline (9a): Color: Yellow. Yield: 78%. M.p.: 183‐185 °C (PhCH3). FT‐IR (KBr, , cm‐1): 3189 (NH), 3055 (CH arom.), 1609, 1596 (C=N). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 6.50 (s, 1H, furyl‐H), 6.63‐6.84 (m, 6 H, furyl‐H, 2 =CH + 3 Ar‐H), 7.18 (d, J = 8.14 Hz, 1 H, Ar‐H), 7.39‐7.47 (m, 3 H, furyl‐H + 2 Ar‐H), 7.76‐7.91 (m, 2 H, Ar‐H), 8.27 (d, J = 8.14 Hz, 1 H, Ar‐H), 9.08 (brs, 2 H, 2 NH). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 168.2 (C), 154.1 (C), 153.4 (C), 144.8 (C), 143.5 (C), 141.3 (CH), 139.8 (CH), 138.3 (CH), 129.2 (2CH), 126.8 (CH), 126.4 (CH), 119.7 (CH), 114.8 (2CH), 114.3 (C), 113.9 (CH), 112.4 (CH), 112.1 (CH), 109.9 (CH). HRMS (EI, m/z) calcd. for C20H16N4O+; calc. 328.1324; found 328.1329. Anal. calcd. for C20H16N4O: C, 73.15; H, 4.91; N, 17.06. Found: C, 73.33; H, 5.04; N, 17.23%. N'‐{2‐[(E)‐2‐(furan‐2‐yl)ethenyl]quinazolin‐4‐yl}‐4‐methyl benzene‐1‐sulfonohydrazide (9b): Color: Yellow. Yield: 76%. M.p.: 294‐296 °C (EtOH). FT‐IR (KBr, n, cm‐1): 3200, 3361 (NH), 3057 (CH arom.), 2942 (CH aliph.), 1614 (C=N), 1183 (SO2). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 2.13 (s, 3 H, CH3), 6.49 (s, 1H, furyl‐H), 6.64‐6.73 (m, 2 H, furyl‐H + =CH), 6.93 (d, J = 15.4 Hz, 1 H, =CH), 7.38‐7.46 (m, 4 H, furyl‐H + 3 Ar‐H), 7.78‐7.85 (m, 3 H, Ar‐H), 8.09‐8.18 (m, 2 H, Ar‐H), 9.14 (brs, 1 H, NH), 9.67 (brs, 1 H, NH). HRMS (EI, m/z) calcd. for C21H18N4O3S, 406.1100; found 406.1107. Anal. calcd. for C21H18N4O3S: C, 62.05; H, 4.46; N, 13.78. Found: C, 62.27; H, 4.35; N, 14.02%. 2.2.9. Synthesis of quinazolines 10a,b Procedure A: A solution of chloro compound 2 (2.57 g, 0.01 mol) and acid hydrazide namely, acetyl hydrazide and/or benzoyl hydrazide (0.015 mol) in glacial acetic acid (20 mL) and 5 mL of freshly distilled acetanhydride was heated at 110 °C for 5 h. The excess solvent was distilled off and the solid that separated after cooling was filtered off, washed with light petroleum ether (B.p. 60‐80 °C), and recrystallized from n‐ butanol to afford compound 10a and 10b, respectively (Scheme 3). Procedure B: A solution of 4‐hydrazinoquinazoline 8 (2.52 g, 0.01 mol) and acid chlorides namely, acetyl chloride and/or benzoyl chloride in freshly distilled acetanhydride (10 132 El‐Badry et al. / European Journal of Chemistry 7 (1) (2016) 128‐134 Scheme 4 mL) was heated in water bath at 70 °C for 3 h. The reaction mixture was cooled and the solid that formed was collected washed with light petroleum ether (B.p.: 60‐80 °C) and crystallized from n‐butanol to give compound 10a and 10b, respectively (Scheme 3). 5‐[(E)‐2‐(furan‐2‐yl)ethenyl]‐3‐methyl[1, 2, 4]triazolo[4, 3‐ c]quinazoline (10a): Color: Yellow. Yield: 84%. M.p.: 297‐298 °C. FT‐IR (KBr, , cm‐1): 3055 (CH arom.), 2938 (CH aliph.), 1619 (C=N). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 2.51 (s, 3 H, CH3), 6.48 (s, 1H, furyl‐H), 6.68‐6.85 (m, 2 H, furyl‐H + =CH), 7.31‐7.43 (m, 2 H, furyl‐H + Ar‐H), 7.76 (d, J = 15.4 Hz, 1 H, =CH), 8.07‐8.11 (m, 2 H, Ar‐H), 8.31 (d, J = 8.14 Hz, 1 H, Ar‐H). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 159.1 (C), 157.3 (C), 151.4 (C), 149.3 (C), 143.9 (CH), 139.6 (CH), 137.1 (C), 133.6 (CH), 127.4 (CH), 126.8 (CH), 123.1 (C), 117.7 (CH), 114.9 (CH), 112.4 (CH), 110.8 (CH), 18.2 (CH3). HRMS (EI, m/z) calcd. for C16H13N4O, 277.1089; found 277.1095. Anal. calcd. for C16H12N4O: C, 69.55; H, 4.38; N, 20.28. Found: C, 69.67; H, 4.52; N, 20.56%. 5‐[(E)‐2‐(furan‐2‐yl)ethenyl]‐3‐phenyl[1, 2, 4]triazolo[4, 3‐ c]quinazoline (10b): Color: Yellow. Yield: 81%. M.p.: 306‐308 °C. FT‐IR (KBr, , cm‐1): 3054 (CH arom.), 1598, 1623 (C=N). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 6.51 (s, 1H, furyl‐H), 6.61‐6.74 (m, 2 H, furyl‐H + =CH), 7.19(t, J = 8.39 Hz, 1 H, Ar‐ H), 7.39‐7.51 (m, 7 H, furyl‐H, =CH + 5 Ar‐H), 7.91‐7.97 (m, 2 H, Ar‐H), 8.19 (d, J = 8.39 Hz, 1 H, Ar‐H). HRMS (EI, m/z) calcd. for C21H15N4O, 339.1246; found 339.1249. Anal. calcd. for C21H14N4O: C, 74.54; H, 4.17; N, 16.56. Found: C, 74.73; H, 4.29; N, 16.81%. 2.2.10. Synthesis of {2‐[(E)‐2‐(furan‐2‐yl)ethenyl] quinazolin‐4‐yl}propanedinitrile (11) A mixture of 4‐chloroquinazoline 2 (2.57 g, 0.01 mol) and malononitrile (0.99 g, 0.015 mol) in dry pyridine (20 mL) was heated under reflux for 2h. The reaction mixture after cooling was poured over HCl/crushed ice. The reaction mixture was concentrated, cooled and the solid obtained was filtered off and recrystallized from EtOH/H2O to give compound 11 (Scheme 4). Color: Reddish brown. Yield: 86%. M.p.: 317‐319 °C. FT‐IR (KBr, , cm‐1): 3061 (CH arom.), 2943 (CH aliph.), 2200, 2220 (CN), 1624 (C=N). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 4.86 (s, 1 H, CH(CN)2), 6.48 (s, 1H, furyl‐H), 6.68‐6.91 (m, 3 H, furyl‐H + 2 =CH), 7.34‐7.45 (m, 2 H, furyl‐H + Ar‐H), 7.98‐8.05 (m, 2 H, Ar‐H), 8.43 (d, J = 8.3 Hz, 1 H, Ar‐H). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 158.7 (C), 150.9 (C), 149.8 (C), 147.1 (C), 143.2 (CH), 139.0 (CH), 137.4 (CH), 129.8 (CH), 126.7 (CH), 119.6 (C), 116.2 (CH), 114.9 (CH), 112.4 (2C), 111.3 (CH), 109.6 (CH), 38.7 (CH). HRMS (EI, m/z) calcd. for C17H10N4O, 286.0855; found 286.0863. Anal. calcd. for C17H10N4O: C, 71.32; H, 3.52; N, 19.57. Found: C, 71.14; H, 3.63; N, 19.36%. 2.2.11. Synthesis of 2‐{2‐[(E)‐2‐(furan‐2‐yl)ethenyl] quinazolin‐4‐yl}propanediamide (12) To a solution of propanedinitrile 11 (3.22 g, 0.01 mol) in a mixture glacial AcOH:EtOH (2:1) a catalytic amount of Zn dust was added and the reaction mixture was heated under reflux for 3 h. The reaction mixture after cooling was poured on ice water and the solid that separated was filtered off and crystallized from EtOH to afford compound 12 (Scheme 4). Color: Beige. Yield: 82%. M.p.: 286‐287 °C. FT‐IR (KBr, , cm‐1): 3200, 3367 (NH), 2937 (CH aliph.), 1684 (CO), 1625 (C=N). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 4.91 (s, 1 H, CH(CONH2)2), 6.51 (s, 1H, furyl‐H), 6.64‐6.82 (m, 3 H, furyl‐H + 2 =CH), 6.90 (brs ,4 H, NH`s), 7.48‐7.59 (m, 3 H, furyl‐H + 2 Ar‐ H), 8.21‐8.33 (m, 2 H, Ar‐H). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 166.6 (2C), 157.2 (C), 153.7 (C), 151.4 (C), 147.2 (C), 140.9 (CH), 137.1 (CH), 132.9 (CH), 127.9 (CH), 126.4 (CH), 121.8 (C), 114.3 (CH), 111.6 (CH), 109.7 (CH), 109.1 (CH), 63.5 (CH). HRMS (EI, m/z) calcd. for C17H14N4O3, 322.1066; found: 322.1073. Anal. calcd. for C17H14N4O3: C, 63.35; H, 4.38; N, 17.38. Found: C, 63.58; H, 4.52; N, 17.16%. 2.2.12. Synthesis of 5‐{2‐[(E)‐2‐(furan‐2‐yl)ethenyl] quinazolin‐4‐yl}‐2‐methylpyrimidine‐4,6(1H,5H)‐dione (13) To a solution of propane diamide 12 (3.22 g, 0.01 mol) in glacial acetic acid (30 mL) a catalytic amount of sod. acetate was added and the reaction mixture was heated under reflux for 4h. The reaction mixture after concentration and cooling, the solid that separated was filtered off and crystallized from EtOH to afford compound 13 (Scheme 4). Color: Beige. Yield: 74%. M.p.: 232‐234 °C. FT‐IR (KBr, , cm‐1): 3216 (NH), 3054 (CH arom.), 2944 (CH aliph.), 1678, 1685 (CO), 1623 El‐Badry et al. / European Journal of Chemistry 7 (1) (2016) 128‐134 133 (C=N). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 2.31 (s, 3 H, CH3), 3.19 (s, 1 H, pyrimidine‐H), 6.49 (s, 1H, furyl‐H), 6.66‐ 6.84 (m, 3 H, furyl‐H + 2 =CH), 7.51‐7.58 (m, 3 H, furyl‐H + 2 Ar‐H), 8.23‐8.31 (m, 2 H, Ar‐H), 9.87 (brs, 1 H, NH). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 181.7 (C), 169.1 (C), 159.2 (C), 156.9 (C), 153.2 (C), 151.4 (C), 146.8 (C), 141.3 (C), 139.8 (CH), 137.6 (CH), 131.2 (CH), 129.0 (CH), 126.8 (CH), 123.4 (CH), 113.8 (CH), 111.7 (CH), 110.7 (CH), 109.2 (CH), 23.9 (CH3). HRMS (EI, m/z) calcd. for C19H14N4O3, 346.1066; found 346.1071. Anal. calcd. for C19H14N4O3: C, 65.89; H, 4.07; N, 16.18. Found: C, 66.11; H, 3.92; N, 15.97%. 3. Results and discussion The key starting material 4‐chloro‐2‐(furan‐2‐yl)‐vinyl‐ quinazoline (2) has been synthesized in good yield via chlorination of the corresponding 4‐oxoquinazoline analog compound 1 (prepared according to a reported method [20]) using a mixture of phosphorus oxychloride and phosphorus pentachloride in boiling water bath (Scheme 1). It was envisioned that compounds like compound 2 are considered as key starting materials for a diversity of heterocyclic compounds [21], since they have a hydrolysable chloroatom which can be easily exchanged. Moreover, 4‐ substituted aminoquinazoline derivatives are exploited as promising pharmacological active agents [22‐23]. Under such circumstance, the interaction of chloroquinazoline 2 with primary amines like 2‐aminothiazole and/or 2‐aminothia diazole afforded the 4‐aryl aminoquinazoline derivatives 3a,b, respectively (Scheme 2). The structure of compounds 3a and b were confirmed from correct analytical data and their spectroscopic analysis, where their FT‐IR spectra displayed strong absorption bands at 3159 and 3164 cm‐1 for NH group, 1H NMR gave bands at δ 9.06 and 9.08 ppm characteristic for D2O exchangeable NH (c.f. experimental section). Sulfa drugs were proven to be of therapeutic importance and are used against a wide spectrum of bacterial elements [24]. Since quinazoline derivatives also have antibacterial activity, it was of interest to incorporate with sulfa drugs in the quinazoline nucleus in order to have promising antibacterial agents. Indeed, the interaction of sulfa drugs such as sulf‐ acetamide and/or sulfaguanidine with chloroquinazoline 2 in 1,4‐dioxane furnished the corresponding 4‐N‐substituted quinazolines 4a,b, respectively (Scheme 2). The IR spectra of compound 4a and b revealed strong absorption bands at 3164, 3189, 3357, and 3368 cm‐1 assignable for NH groups, 1H NMR spectra substantiated signals for each compound at δ 8.68, 8.93, and 9.30 ppm expected for sulfonamide NH's and NH groups respectively (c.f. experimental section). Condensation of 4‐chloroquinazoline derivative 2 with secondary amines namely morpholine and piperazine in boiling ethanol afforded the 4‐arylquinazoline derivatives 5a,b, respectively. While the bisquinazoline piperazine 6 was resulted when the stiochmeteric ratio are changed and the reaction was conducted in glacial acetic acid Structures of compound 5a,b and 6 were elucidated from their spectral and elemental data (c.f. Scheme 2 and experimental section). Some of the 1,2,4‐triazole containing compounds are reported to have anticonvulsants and muscle relaxant activi‐ ties [25]. Incorporate 1,2,4‐triazole moiety at 4 position of quinazoline derivatives is proven as a new class of H1‐ antihistaminic [26]. In this respects, a successful attempt for synthesizing 1,2,4‐trizole‐quinazoline derivatives was achieved via a one‐pot reaction, where the hydrazinolysis of chloroquinazoline 2 and subsequent condensation with different aromatic aldehydes, namely salicylaldehyde, 4‐ methoxy benzaldehyde, and cinnamaldehyde furnished a series of 5‐substituted trizolo‐quinazolines 7a‐c. Additionally, the course of such reaction is chemically investigated via generating the 4‐hydrazino‐quinazoline system 8 as an isolated intermediate. Thereafter, the obtained hydrazine quinazoline 8 was submitted to react with the above‐ mentioned aromatic aldehydes and the 5‐substituted triazolo‐ quinazolines 7a‐c were attained, elemental analysis and spectral data for compounds 7a‐c were found to be in full agreement with the proposed structures. IR spectrum of compound 7a revealed broad absorption band at 3448 cm‐1 corresponding to the hydroxyl group. In addition, 13C NMR of compound 7b showed a resonated signals at δ 159.4, 154.7, and 151.3 ppm attributed to C‐OMe, C=N of triazoloquina‐ zoline, and C=N of C2 quinazoline. On the other hand, IR spect‐ rum of hydrazinoquinazoline compound 8 revealed two absorption bands at 3168 and 3305 cm‐1 confirming the two NH groups. 1H NMR and 13C NMR data afforded a further evidence of the structure. Its 1H NMR displayed signal at δ 4.87ppm attributable to NH`s. 13C NMR of compound 8 showed a resonated signals at δ 161.5, 154.9, and 153.8 ppm attri‐ butable to C‐NH, C=N, and C‐O (c.f. Scheme 3 and experimental section). A similar hydrazinolysis of chloroquinazoline 2 using phenyl hydrazine and/or sulphonyl hydrazine in boiling ethanol afforded 4‐N‐substituted quinazoline derivatives 9a,b (Scheme 3). The IR and 1H NMR spectra for both compound 9a and b exhibited the characteristic signals for the NH groups, HRMS, 13C NMR and elemental analysis confirmed their structures. In the same fashion, the reaction of chloro‐ quinazoline 2 with acid hydrazides like acetyl and/or benzoyl hydrazides in a mixture of glacial acetic acid and freshly distilled acetanhydride (4:1) at 120 °C has afforded new interesting triazoloquinazoline derivatives 10a,b, respectively. IR spectrum of compound 9b recorded the absorption band at 3361, 3200 cm‐1 attributted to NH`s, in addition at 1614 and 1183 cm‐1 attributed to C=N and SO2. 1H NMR spectrum of compound 9b displayed signals at δ 2.13, 9.14, and 9.67 ppm attributable to CH3 and NH`s. On the other hand, IR spectra of compounds 10a,b revealed strong absorption bands at 1598, 1619, and 1623 cm‐1 attributed to C=N. 13C NMR of compound 10a showed a resonated signals at δ 159.1, 157.3, and 153.4 ppm attributable to C4 quinazoline, C=N (C2 quinazoline), and C‐O (c.f. Scheme 3 and experimental section). It is worthwhile to investigate the behavior of our chloroquinazoline system 2 towards carbon nucleophiles. Indeed, the interaction of chloroquinazoline 2 with malono‐ nitrile was conducted in dry pyridine and the 4‐substituted quinazoline 11 was furnished. IR spectrum for compound 11 displayed two absorption bands at νmax 2200 and 2220 cm‐1 assignable for the two C≡N groups. 1H NMR spectrum of compound 11 displayed signal at δ 4.86 ppm attributable to CH(CN)2. Its 13C NMR spectrum showed a resonated signal at δ 38.7 ppm attributable to CH of malononitrile. Partial hydrolysis of the two cyano groups of compound 11 into amides using acetic acid/ethanol mixture and a catalytic amount of Zn dust gave quinazoline derivative 12. Former structure of compound 12 has been deduced from the corrected elemental analysis and spectral data. IR spectrum of compound 12 exhibited strong absorption band at 1684 cm‐1 due to amide group and at 3200 and 3367 cm‐1 attributed to NH2 absorption. Its 1H NMR gave resonated band at δ 6.90 ppm characteristic for D2O exchangeable NH. 13C NMR of compound 12 showed a resonated signal at δ 166.6 ppm attributable to CO amide. Finally, quinazoline derivative 12 was submitted to hetero‐ring cyclization and afforded the interesting spiro compound pyrimidine‐quinazoline derivative 13. The IR spectrum of compound 13 showed strong absorption bands at νmax = 1678, 1685 cm‐1 for the 2C=O groups and at 3216 cm‐1 for the NH group, 1H NMR and 13C NMR data were carried out also and were found to be consistent with the proposed structure for compound 13. Its 1H NMR gave resonated signals at δ 2.31 and 3.19 ppm characteristic for CH3 and pyrimidine‐H. 13C NMR of compound 13 revealed a resonated signal at δ 181.7, 169.1, and 159.2 134 El‐Badry et al. / European Journal of Chemistry 7 (1) (2016) 128‐134 ppm attributed to 2C=O and C=N (c.f. Scheme 4 and experimental section). 4. Conclusion We successfully obtained a novel series of 4‐heteroaryl quinazolines as well as triazolo quinazolines and spiro compound 13 via the simple replacement of the chlorine atom at 4 position of quinazoline nucleus with different amines, hydrazines, and nitriles respectively. Such interesting functionalized quinazoline derivatives obtained are promising anticipated biological activities. Acknowledgements The authors are thankful to Chemistry department, Dortmund Technological University, Germany, for providing FT‐IR, 1H NMR, 13C NMR, and HR‐MS spectral facilities. References [1]. Genady, A. R. Eur. J. Med. Chem. 2009, 44, 409‐416. [2]. Alagarsamy, V. Pharmazie 2004, 59, 753‐755. [3]. Grover, G.; Kini, S. G. Eur. J. Med. Chem. 2006, 41, 256‐262. [4]. Wada, J. J. U. S. Patent No. 4, 528288, Chem. Abstr. 1986, 104, 5889‐ 5889. [5]. Alagarsamy, V.; Shankar, D.; Murugesan, S. Biomed. Pharamacoether. 2008, 62, 173‐178. [6]. He, J.; Wang, X.; Zhao, X.; Liang, Y. J.; He, H.; Fu, L. Eur. J. Med. Chem. 2012, 54, 925‐930. [7]. Li, J.; Zhang, Q.; Jia, Z.; Zhou, B.; Cui, N.; Liang, X. PCT Int, Appl. (2013), WO2013170757 A1 20131121. [8]. Haffner, C. D.; Becherer, J. D. Boros, E. E.; Cadilla, R.; Carpenter, T.; Cowan, D.; Deaton, D. N.; Guo, Y.; Harrington, W.; Henke, B. R. J. Med. Chem. 2015, 58(8), 3548‐3571. [9]. Mott, B. T.; Tanega, C.; Shen, M.; Maloney, D. J.; Shinn, P.; Leister, W.; Marugan, J. J.; Inglese, J.; Austin, C. P.; Mistelli, T. Bioorg. Med. Chem. Let. 2009, 19(23), 6700‐6705. [10]. Holladay, M. W.; Setti, E.; U. S. Patent Appl. Publ. (2012), US20120053193 A1 20130301. [11]. El‐Hashash, M. A.; Guirguis, D. B.; El‐Badry, Y. A. Der Pharma Chemica 2011, 3(6), 147‐159. [12]. El‐Badry, Y. A.; Anter, N. A.; El‐Sheshtawy, H. S. Der Pharma Chemica 2012, 4(3), 1361‐1370. [13]. Carson, D. A.; Cottam, H. B.; Howard, B.; Hayashi, T.; Nour, A.; U. S. Pat. Appl. Publ. (2015), US 20150132342 A1 20150514. [14]. Armstrong, R. C.; Belli, B.; Holladay, M. W.; Rowbottom, M. W.; U. S. Pat. Appl. Publ. (2012), US 20120053176 A1 20120301. [15]. El‐Hashash, M. A.; Abdel‐Rahman, T. M.; El‐Badry, Y. A. Ind. J. Chem. B 2006, 45, 1470‐1477. [16]. El‐Badry, Y. A. Acta Chim. Slov. 2010, 57, 836‐841. [17]. El‐Hashash, M. A.; El‐Badry, Y. A. Helv. Chim. Acta 2011, 94, 389‐396. [18]. El‐Badry, Y. A.; El‐Farragy, A. F.; Eilbracht, P. Helv. Chim. Acta 2013, 96(9), 1782‐1792. [19]. El‐Hashash, M. A.; El‐Badry, Y. A. J. Adv. Chem. 2013, 4(3), 548‐553. [20]. El‐Badry, Y. A.; Anter, N. A.; El‐Hashash, M. A. Ind. J. Chem. B 2014, 53, 1574‐1583. [21]. Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.; Greenwood, T. D. J. Med. Chem. 1990, 33, 161‐166. [22]. Hosam, A. S.; Nermen, A. O. , Ahmed, H. M. Molecules 2011, 16, 10187‐10201. [23]. Kundu, S. K.; Mahindaralne, M. P. D.; Quintero, M. V.; Bao, A.; Negrete, G. R. Arkivoc 2008, 2, 33‐42. [24]. Madkour, H. M. F.; Soliman, E. A.; Salem, M. A. I.; El‐Bordainy, E. A. A. Bull. Pol. Acad. Sci. 1999, 47, 218‐223. [25]. Almasirad, A.; Vousooghi, N.; Tabatabai, S. A.; Kebriaeezadeh, A.; Shafiee, A. Acta Chim. Solv. 2007, 54, 317‐324. [26]. Alagarsamy, V.; Solomon, V. R.; Murugan, M. Bioorg. Med. Chem. 2007, 15, 4009‐4015.