untitled European Journal of Chemistry 6 (1) (2015) 63‐70 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2015 Atlanta Publishing House LLC ‐ All rights reserved ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.6.1.63‐70.1147 European Journal of Chemistry Journal webpage: www.eurjchem.com Synthesis of some new fluorine substituted thiobarbituric acid derivatives as anti HIV1 and cyclin‐dependent kinase 2 (CDK2) for cell tumor division: Part I Abdulrahman Salim Al‐Harbi 1,*, Reda Mohammady Abdel‐Rahman 1 and Abdullah Mohamed Asiri 1,2 1 Department of Chemistry, Faculty of Science, King Abdul Aziz University, Jeddah, 21589, Kingdom of Saudi Arabia 2 Centre of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia * Corresponding author at: Department of Chemistry, Faculty of Science, King Abdul Aziz University, Jeddah, 21589, Kingdom of Saudi Arabia. Tel.: +966.12.6859154. Fax: +966.12.6952292. E‐mail address: magiceyes2002@hotmail.com (A.S. Al‐Harbi). ARTICLE INFORMATION ABSTRACT DOI: 10.5155/eurjchem.6.1.63‐70.1147 Received: 11 September 2014 Received in revised form: 13 October 2014 Accepted: 18 October 2014 Published online: 31 March 2015 Printed: 31 March 2015 New potential enzyme inhibitors, fluorine‐substituted thiobarbituric acid derivatives (2, 3, 9, 8 and 12) and their fused/isolated heterocyclic nitrogen systems (5, 6, 10 and 14) have been obtained from heterocyclization of fluorinated N, Nʹ‐disubstituted thiourea (1, 7 and 11) with malonic acid followed by ring closure reactions with primary nitrogen reagents. Structures of the synthesized products have been deduced from their elemental analysis and spectral data. Anti‐HIV‐1 and inhibition of cyclin‐dependent kinase2 (CDK2) for cell tumor division for the synthesized compounds were also evaluated. KEYWORDS CDK2 Anti HIV Synthesis Heterocyclic Potential inhibitors Fluorinated thiobarbituric Cite this: Eur. J. Chem. 2015, 6(1), 63‐70 1. Introduction Increased use of anti‐HIV1 and anti‐AIDS agents in recent years have been resulted in the development of resistance to commercially available drugs [1‐3]. Thiobarbituric acids have been reported to possess interesting biological and pharmacological activities [4‐7] including the inhibitors of hepatitis C virus NS5B polymerase [8], against nonalcoholic fatty liver disease [9], potent anticonvulsant [10], measured auto‐oxidation of brain homogenates from various animals [11], determining formaldehyde and acetaldehyde in food [12], HIV‐1 integrate inhibitors [13] and decreases liquid peroxide in human plasma [14,15]. The introduction of fluorine atoms to bioactive molecules enhance and improve their pharma‐ cological properties [16‐18]. Also, presence of hetero‐atoms increased membrane, permeability, which enhances the electrostatic force and hydrophobic binding stability against metabolic transformations [18‐22]. As part of the interested research program in the fluorine substituted heterocyclic nitrogen systems as biocidal agents [23‐27], the present work tends to synthesize, some new fluorinated‐thiobarbituric acids full fused in view of their anti‐HIV and cyclin‐dependent kinase 2. 2. Experimental 2.1. Instrumentation Melting points determined with an electrothermal Bibly Stuart Scientific melting point Sample (UK). A Perkin Elmer Model RXI‐FT IR system 55529 was used for recording IR spectra of the prepared compounds. A Bruker advance DPX 400 MHz model uses TMS as internal standard was used for recording the 1H and 13C NMR spectra of the compounds on deuterated CDCl3. A GC‐MS‐GP 1000 Ex model used for recording the mass spectra of the compounds. Electronic spectra recorded in ethanol on Shimadzu UV and visible 310 IPC Spectrophotometer. Elemental analyses were performed in microanalytical Center of Cairo University, Egypt. 2.2. Synthesis 2.2.1. Synthesis of compounds 1a‐c Equimolar amounts of 4‐fluoroaniline (0.001 mol) and aryl isothiocyanates (0.001 mol) were warmed in THF for 1 h then cooled. The solid product was filtered off and crystallized from ethanol to give compound 1a‐c as yellow crystals (Scheme 1). 64 Al‐Harbi et al. / European Journal of Chemistry 6 (1) (2015) 63‐70 Scheme 1 1‐(4‐Fluorophenyl)‐3‐phenylthiourea (1a): Color: Yellow. Yield: 78%. M.p.: 140‐141 °C. FT‐IR (KBr, , cm‐1): 3180 (NH), 1385 (cyclic NCSN), 1255 (C‐F), 1210 (C=S), 864 (Aryl‐CH), 657 (C‐F). MS (EI, m/z (%)): 247 (M+1, 100). UV/Vis (EtOH, λmax, nm, (ɛ)): 238 (0.877). Anal. calcd. for C13H11FN2S: C, 63.39; H, 4.50; N, 11.37; S, 13.02. Found: C, 63.11; H, 4.44; N, 11.20; S, 13.01%. 1‐(4‐Bromophenyl)‐3‐(4‐fluorophenyl)thiourea (1b): Color: Yellow. Yield: 82%. M.p.: 160‐161 °C. FT‐IR (KBr, , cm‐1): 3200 (NH), 1380 (Cyclic NCSN), 1250 (C‐F), 1190 (C=S), 900 (Aryl‐CH), 650 (C‐F). MS (EI, m/z (%)): 325.90 (100). UV/Vis (EtOH, λmax, nm, (ɛ)): 275 (0.95). Anal. calcd. for C13H10BrFN2S: C, 48.01; H, 3.10; N, 8.61; S, 9.86. Found: C, 47.89; H, 2.88; N, 8.41; S, 9.66%. 1‐(4‐Chlorophenyl)‐3‐(4‐fluorophenyl)thiourea (1c): Color: Yellow. Yield: 87%. M.p.: 162‐164 °C. FT‐IR (KBr, , cm‐1): 3210 (NH), 1370 (Cyclic NCSN), 1260 (C‐F), 1185 (C=S), 850 (Aryl‐CH), 700 (C‐Cl), 660 (C‐F). MS (EI, m/z (%)): 280.32 (M+, 100). UV/Vis (EtOH, λmax, nm, (ɛ)): 310 (1.20). Anal. calcd. for C13H10ClFN2S: C, 55.62; H, 3.59; N, 9.98; S, 11.42. Found: C, 54.43; H, 3.22; N, 9.40; S, 10.91%. 2.2.2. Synthesis of compounds 2a‐c A mixture of compound 1a‐c (0.001 mol) and malonic acid (0.001 mol) in a few drops of acetyl chloride and glacial acetic acid (20 mL) was refluxed for 2h then poured onto ice. The solid product was filtered off and crystallized from dioxan to give compounds 2a‐c as yellow crystals (Scheme 1). 1‐(4‐Fluorophenyl)‐3‐phenyl‐2‐thioxodihydropyrimidine‐4,6 (1H,5H)‐dione (2a): Color: Yellow. Yield: 75%. M.p.: 86‐88 °C. FT‐IR (KBr, , cm‐1): 3476 (OH), 2856 (Str. CH2), 1680 (C=O), 1497 (Deform. CH2), 1387 (Cyclic NCSN), 1255 (C‐F), 1180 (C=S), 864 (Aryl CH), 659 (C‐F). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.59‐2.58 (s, 2H, CH2), 7.96‐7.01 (m, 9H, Ar‐H), 9.81 (s, 1H, OH). 13C NMR (100 MHz, CDCl3, δ, ppm): 166.32, 159.75, 158.17, 135.15, 135.10, 135.08, 128.29, 127.69, 122.37, 115.20, 115.05, 77.81, 40.43. MS (EI, m/z (%)): 314 (M+, 100). UV/Vis (EtOH, λmax, nm, (ɛ)): 258 (0.984). Anal. calcd. for C16H11FN2O2S: C, 61.14; H, 3.53; N, 8.91; S, 10.20. Found: C, 61.10; H, 3.35; N, 8.69; S, 10.00%. 1‐(4‐Bromophenyl)‐3‐(4‐fluorophenyl)‐2‐thioxodihydropyri midine‐4,6(1H,5H)‐dione (2b): Color: Yellow. Yield: 78%. M.p.: 120‐122 °C. FT‐IR (KBr, , cm‐1): 3500 (OH), 2852 (Str. CH2), 1700 (C=O), 1488 (Deform. CH2), 1380 (Cyclic NCSN), 1188 (C=S), 800 (Aryl CH), 710 (C‐Br), 680 (C‐F). MS (EI, m/z (%)): 394.1 (M+1, 95). UV/Vis (EtOH, λmax, nm, (ɛ)): 345 (1.88). Anal. calcd. for C16H10BrFN2O2S: C, 48.87; H, 2.56; N, 7.12; S, 8.14. Found: C, 48.58; H, 2.41; N, 7.01; S, 8.00%. 1‐(4‐Chlorophenyl)‐3‐(4‐fluorophenyl)‐2‐thioxodihydropyri midine‐4,6(1H,5H)‐dione (2c): Color: Yellow. Yield: 81%. M.p.: 116‐118 °C. FT‐IR (KBr, , cm‐1): 3410 (OH), 2848 (Str. CH2), 1675 (C=O), 1445 (Deform. CH2), 1370 (Cyclic NCSN), 1188 (C=S), 870 (Aryl CH), 700 (C‐Br), 676 (C‐F). UV/Vis (EtOH, λmax, Al‐Harbi et al. / European Journal of Chemistry 6 (1) (2015) 63‐70 65 nm, (ɛ)): 375 (0.98). MS (EI, m/z (%)): 348 (100). Anal. calcd. for C16H10ClFN2O2S: C, 55.10; H, 2.89; N, 8.03; S, 9.19. Found: C, 54.83; H, 2.66; N, 7.89; S, 8.77%. 2.2.3. Synthesis of compound 3 A mixture of compound 2a (0.001 mol) and cyclohexyl isocyanate (0.001 mol) in ethanol (20 mL) with a piperidine (0.5 mL) was refluxed for 8 h, cooled, and concentrated. The solid product was crystallized from dioxan to give compound 3 as white crystals (Scheme 1). 1‐(4`‐Fluorophenyl)‐3‐(phenyl)‐5‐(cyclohexylcarbamido)‐2, 3‐dihydro‐2‐thioxo‐4,6‐(1H,5H) pyrimidine‐dione (3): Color: White. Yield: 75%. M.p.: 98‐99 °C. FT‐IR (KBr, , cm‐1): 3492 (OH), 3180 (NH), 1668 (C=O), 1502 (Deform. CH2), 1386 (Cyclic NCSN), 1255 (C‐F), 1180 (C=S), 864 (Aryl CH), 659 (C‐ F). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.14‐2.02 (s, 11H, CH2+CH), 7.95‐7.00 (m, 5H, C6H5), 8.02‐8.11 (m, 4H, Ar‐H), 8.95 (s, 1H, NH), 10.5 (s, 1H, OH). MS (EI, m/z (%)): 439(M+, 49). UV/Vis (EtOH, λmax, nm, (ɛ)): 275. Anal. calcd. for C23H22FN3O3S: C, 62.85; H, 5.05; N, 9.56; S, 7.30. Found: C, 62.51; H, 4.88; N, 9.39; S, 7.01%. 2.2.4. Synthesis of compound 4 Compound 3 (0.050 mol) in glacial acetic acid (10 mL) and anhydrous sodium acetate (0.50 g) was refluxed for 2 h cooled and poured onto ice. The solid product was filtered off, then crystallized from ethanol to give compound 4 as yellowish brown crystals (Scheme 1). 8‐Cyclohexyl‐2‐(4‐fluorophenyl)‐4‐phenyl‐3‐thioxo‐2,4,8‐tri azabicyclo[4.2.0]oct‐1(6)‐ene‐5,7‐dione (4): Color: Yellowish brown. Yield: 80%. M.p.: 110‐112 °C. FT‐IR (KBr, , cm‐1): 1710, 1680 (C=O), 1500 (Deform. CH2), 1382 (Cyclic NCSN), 1255 (C‐F), 1181 (C=S), 864 (Aryl CH), 657 (C‐F). 1H NMR (400 MHz, CD3Cl, δ, ppm): 2.22‐2.01 (s, 11H, CH2+CH), 7.70‐7.10 (m, 5H, Ar‐H), 8.12‐8.02 (m, 4H, Ar‐H). MS (EI, m/z (%)): 422 (M+, 25.13). UV/Vis (EtOH, λmax, nm, (ɛ)): 278 (0.88). Anal. calcd. for C23H20FN3O2S: C, 65.54; H, 4.78; N, 9.97; S, 7.61. Found: C, 65.28; H, 4.55; N, 9.77; S, 7.42%. 2.2.5. Synthesis of compounds 5 and 6 A mixture of compound 3 (0.001 mol) and N‐ methyl/phenyl thioureas (0.001 mol) in ethanolic sodium hydoxide (25 mL, 5%) was refluxed for 2 h, cooled then poured into ice‐HCl. The solid product was filtered off, washed with cold water and crystallized from ethanol to give compound 5 and 6, respectively (Scheme 1). 5‐(Cyclohexylamino)‐1‐(4‐fluorophenyl)‐6‐methyl‐3‐phenyl‐ 2,7‐dithioxo‐2,3,6,7‐tetrahydropyrimido[4,5‐d]pyrimidin‐4(1H)‐ one (5): Color: Yellow. Yield: 66%. M.p.: 218‐220 °C. FT‐IR (KBr, , cm‐1): 3119 (NH), 1659 (C=O), 1500, 1441 (Deform. CH2), 1384 (Cyclic NCSN), 1253 (C‐F), 1184 (C=S), 863 (Aryl CH), 657 (C‐F). MS (EI, m/z (%)): 492.90 (M+, 46). UV/Vis (EtOH, λmax, nm, (ɛ)): 315 (1.28). Anal. calcd. for C25H24FN5OS2: C, 60.83; H, 4.90; N, 14.19; S, 12.99. Found: C, 60.59; H, 4.60; N, 14.01; S, 12.39%. 5‐(Cyclohexylamino)‐1‐(4‐fluorophenyl)‐3, 6‐diphenyl‐2, 7‐ dithioxo‐2,3,6,7‐tetrahydropyrimido[4,5‐d] pyrimidin‐4(1H)‐one (6): Color: Yellow. Yield: 75%. M.p.: 130‐132 °C. FT‐IR (KBr, , cm‐1): 3123 (NH), 1661 (C=O), 1499, 1438 (Deform. CH2), 1386 (Cyclic NCSN), 1255 (C‐F), 1185 (C=S), 864 (Aryl CH), 658 (C‐ F). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.59‐2.60 (m, 10H, 5CH2 of cyclohexane), 2.95‐2.96 (s, 1H, CH), 7.96‐7.49 (m, 14H, Ar‐ H), 11.55 (s, 1H, NH). 13C NMR (100 MHz, CDCl3, δ, ppm): 207.02 (C=S), 157.10 (C=O), 130.01‐126.01 (Ar‐C). MS (EI, m/z (%)): 554.85 (79). UV/Vis (EtOH, λmax, nm, (ɛ)): 287 (1.12). Anal. calcd. for C30H26FN5OS2: C, 64.84; H, 4.72; N, 12.60; S, 11.54. Found: C, 64.26; H, 4.51; N, 12.33; S, 11.31%. 2.2.6. Synthesis of compounds 7a‐c A mixture of benzoyl isothiocyanate (0.001 mol) and sulfa‐ drugs, namely sulfathiazole, sulfamerazine or sulfadiazine (0.001 mol) in THF (20 mL) was refluxed for 1 h, cooled. The solid product was filtered off and crystallized from THF to give compounds 7a‐c as yellow crystals (Scheme 2). N‐((4‐(N‐(Thiazol‐2‐yl) sulfamoyl) phenyl) carbamothioyl) benzamide (7a): Color: Yellow. Yield: 89%. M.p.: 218‐219 °C. FT‐IR (KBr, , cm‐1): 3300‐3100 (NH‐NH), 3005 (Aryl CH), 1580 (NHCO), 1499, 1386 ( NCSN), 1218 (C=S), 865 (Aryl CH). 1H NMR (400 MHz, CDCl3, δ, ppm): 4.23 (s, 1H, NH), 7.99‐7.88, 7.65‐6.00 (each m, 11H, Ar‐H), 10.70 (s, 1H, NH), 13.07 (s, 1H, NH). 13C NMR (100 MHz, CDCl3, δ, ppm): 179.16, 169.24, 168.37, 140.92, 139.82, 131.70, 128.73, 128.11, 126.91, 123.68, 123.59, 107.51, 77.80, 67.76, 40.44‐39.49, 25.44. MS (EI, m/z (%)): 418.31 (100). UV/Vis (EtOH, λmax, nm, (ɛ)): 238. Anal. calcd. for C17H14N4O3S3: C, 48.79; H, 3.37; N, 13.39; S, 22.98. Found: C, 48.59; H, 3.21; N, 13.25; S, 22.59%. N‐((4‐(N‐(4‐Methylpyrimidin‐2‐yl) sulfamoyl) phenyl) carba mothioyl)benzamide (7b): Color: Yellow. Yield: 86%. M.p.: 196‐ 197 °C. FT‐IR (KBr, , cm‐1): 3300‐3100 (NH‐NH), 2910 (Str. CH3), 1610 (C=N), 1590 (NHCO), 1480 (Deform. CH3), 1380 (Acyclic. NCSN), 1350 (SO2NH), 1188 (C=S), 850, 810 (Aryl CH). MS (EI, m/z (%)): 427 (100). UV/Vis (EtOH, λmax, nm, (ɛ)): 266 (1.11). Anal. calcd. for C19H17N5O3S2: C, 53.38; H, 4.01; N, 16.38; S, 15.00. Found: C, 53.20; H, 3.69; N, 16.11; S, 14.68%. N‐((4‐(N‐(Pyrimidin‐2‐yl)sulfamoyl) phenyl) carbamothioyl) benzamide (7c): Color: Yellow. Yield: 82%. M.p.: 150‐151 °C. FT‐IR (KBr, , cm‐1): 3280‐3090 (NH‐NH), 1625 (C=N), 1600 (NHCO), 1388 (Acyclic. NCSN), 1340 (SO2NH), 1190 (C=S), 880, 815 (Aryl CH). MS (EI, m/z (%)): 412.56 (100). UV/Vis (EtOH, λmax, nm, (ɛ)): 269 (0.66). Anal. calcd. for C18H15N5O3S2: C, 52.29; H, 3.66; N, 16.94; S, 15.51. Found: C, 52.09; H, 3.55; N, 16.48; S, 15.32%. 2.2.7. Synthesis of compounds 8a‐c A mixture of compounds 7a‐c (0.001 mol), malonic acid (0.001 mol) in acetyl chloride (drops) and glacial acetic acid (20 mL) was refluxed for 2 h, cooled and concentrated. The solid product was crystallized from 1,4‐dioxan to give compounds 8a‐c as yellow crystals (Scheme 2). 4‐(3‐Benzoyl‐4,6‐dioxo‐2‐thioxotetrahydropyrimidin‐1(2H)‐ yl)‐N‐(thiazol‐2‐yl)benzenesulfonamide (8a): Color: Yellow. Yield: 71%. M.p.: 190‐191 °C. FT‐IR (KBr, , cm‐1): 3540 (OH), 3100 (NH), 1661 (C=O), 1502 (Deform. CH2), 1438 (Deform. CH2), 1385 (NCSN), 1147 (C=S), 929 (aryl CH). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.60‐2.21 (m, 2H, CH2), 6.93‐7.52, (m, 11H, aromatic), 11.28 (s, 1H, OH), 12.84 (s, 1H, NH). 13C NMR (100 MHz, CDCl3, δ, ppm): 179.26, 173.06, 169.22, 140.96, 139.52, 126.84, 123.67, 123.44, 107.50, 123.68, 77.75‐77.36, 40.42‐39.47, 24.08. MS (EI, m/z (%)): 485.94 (23). UV/Vis (EtOH, λmax, nm, (ɛ)): 280 (0.246). Anal. calcd. for C20H14N4O5S3: C, 49.37; H, 2.90; N, 11.52; S, 19.77. Found: C, 49.21; H, 2.77; N, 11.28; S, 19.58%. 4‐(3‐Benzoyl‐4,6‐dioxo‐2‐thioxotetrahydropyrimidin‐1(2H)‐ yl)‐N‐(4‐methylpyrimidin‐2‐yl)benzenesulfon amide (8b): Color: Yellow. Yield: 76%. M.p.: 250‐251 °C. FT‐IR (KBr, , cm‐1): 3545 (OH), 3100 (NH), 2912 (Str. CH3),1667 (C=O), 1500 (Deform. CH2), 1384 (NCSN), 1357 (SO2NH) 1144 (C=S), 923 (aryl CH). MS (EI, m/z (%)): 494.51 (47). UV/Vis (EtOH, λmax, nm, (ɛ)): 305 (0.95). Anal. calcd. for C22H17N5O5S2: C, 53.32; H, 3.46; N, 14.13; S, 12.94. Found: C, 53.21; H, 3.21; N, 14.00; S, 12.80%. 4‐(3‐Benzoyl‐4,6‐dioxo‐2‐thioxotetrahydropyrimidin‐1(2H)‐ yl)‐N‐(pyrimidin‐2‐yl)benzenesulfonamide (8c): Color: Yellow. Yield: 72%. M.p.: 224‐226 °C. FT‐IR (KBr, , cm‐1): 3547 (OH), 3104 (NH), 1667 (C=O), 1507 (Deform. CH2), 1386 (NCSN), 1355 (SO2NH), 1147 (C=S), 920 (Aryl CH). 66 Al‐Harbi et al. / European Journal of Chemistry 6 (1) (2015) 63‐70 Scheme 2 MS (EI, m/z (%)): 480.25 (46). UV/Vis (EtOH, λmax, nm, (ɛ)): 315 (1.15). Anal. calcd. for C21H15N5O5S2 : C, 52.38; H, 3.14; N, 14.54; S, 13.32. Found: C, 52.15; H, 3.01; N, 14.31; S, 13.09%. 2.2.8. Synthesis of compounds 9a and b To compound 8a and 8b (0.001 mol) in DMF (20 mL) 4‐ fluorobenzoyl chloride (0.001 mol) was added and warmed for 1h, cooled and poured onto ice. The solid product was crystallized from 1,4‐dioxan to give compounds 9a and 9b as yellow crystals (Scheme 2). 4‐(3‐Benzoyl‐5‐(4‐fluorobenzoyl)‐ 4,6‐dioxo‐2‐thioxotetra hydropyrimidin‐1(2H)‐yl)‐N‐(thiazol‐2‐yl)benzene sulfonamide (9a): Color: Yellow. Yield: 66%. M.p.: 172‐173 °C. FT‐IR (KBr, , cm‐1): 3528 (OH), 1680, 1660 (C=O), 1385 (NCSN), 1255 (C‐ F), 1180 (C=S), 864 (Aryl CH), 658 (C‐F). 1H NMR (400 MHz, CD3Cl, δ, ppm): 7.39‐8.05 (m, 15H, Ar‐H), 8.51 (s, 1H, OH), 9.80 (s, 1H, NH). 13C NMR (100 MHz, CDCl3, δ, ppm): 167.52, 166.37, 164.69, 132.29, 132.23, 127.21, 127.19, 77.50‐77.08, 40.44‐ 39.54. MS (EI, m/z (%)): 607.89 (100). UV/Vis (EtOH, λmax, nm, (ɛ)): 244 (0.1035). Anal. calcd. for C27H17FN4O6S3: C, 53.28; H, 2.82; F, 3.12; N, 9.21; S, 15.80. Found: C, 53.01; H, 2.66; N, 9.11; S, 15.58%. 4‐(3‐Benzoyl‐5‐(4‐fluorobenzoyl)‐ 4, 6‐dioxo‐2‐thioxotetra hydropyrimidin‐1 (2H)‐yl)‐N‐(4‐methylpyrimidin‐2‐yl) benzene sulfon amide (9b): Color: Yellow. Yield: 68%. M.p.: 159‐160 °C. FT‐IR (KBr, , cm‐1): 3480 (OH), 1700, 1670 (C=O), 1590 (C=N), 1360 (NCSN), 1330 (SO2NH), 1250 (C‐F), 1188 (C=S), 850,820 (Aryl CH), 660 (C‐F). MS (EI, m/z (%)): 616.85 (0.43). UV/Vis (EtOH, λmax, nm, (ɛ)): 265 (0.110). Anal. calcd. for C29H20FN5O6S2: C, 56.39; H, 3.26; N, 11.34; S, 10.38. Found: C, 56.27; H, 3.08; N, 11.32; S, 10.21%. 2.2.9. Synthesis of compounds 10a and b A mixture of compounds 9a and 9b (0.001 mol) and 4‐ chlorophenyl hydrazine.HCl (0.001 mol in 5 mL H2O) in absolute ethanol (20 mL) and sodium acetate (0.001 mol) was refluxed for 4 h, cooled and poured onto ice. Al‐Harbi et al. / European Journal of Chemistry 6 (1) (2015) 63‐70 67 Scheme 3 The solid product was filtered off and crystallized from ethanol to give compounds 10a and or 10b as yellow crystals (Scheme 2). 4‐(7‐Benzoyl‐2‐(4‐chlorophenyl)‐3‐(4‐fluorophenyl)‐4‐oxo‐ 6‐thioxo‐6,7‐dihydro‐2H‐pyrazolo[3,4‐d]pyrimidin‐5(4H)‐yl)‐N‐ (thiazol‐2‐yl)benzenesulfonamide (10a): Color: Yellow. Yield: 55%. M.p.: 131‐132 °C. FT‐IR (KBr, , cm‐1): 3120 (NH), 1662 (C=O), 1580 (C=N), 1385 (NCSN), 1340 (SO2NH), 1255 (C‐F), 1180 (C=S), 865 (Aryl CH), 710 (C‐Cl), 657 (C‐F). 1H NMR (400 MHz, CDCl3, δ, ppm): 4.30 (s, 1H, NH), 7.11‐6.72 (d, 2H, Thiazol), 7.16‐7.15 (m, 5H, phenyl), 7.29‐7.27 (d, 4H, 4‐chloro phenyl), 7.53‐7.47 (d, 4H, Ar‐H), 8.20‐7.51 (d, 4H, 4‐fluoro phenyl). 13C NMR (100 MHz, CDCl3, δ, ppm): 176.72, 170.30, 147.50, 146.90, 128.94, 128.68, 124.29, 114.39, 113.49, 77.82, 40.41. MS (EI, m/z (%)): 714.01 (92). UV/Vis (EtOH, λmax, nm, (ɛ)): 315 (0.1118). Anal. calcd. for C33H20ClFN6O4S3: C, 55.42; H, 2.82; N, 11.75; S, 13.45. Found: C, 55.23; H, 2.55; N, 11.56; S, 13.20%. 4‐(7‐Benzoyl‐2‐(4‐chlorophenyl)‐3‐(4‐fluorophenyl)‐4‐oxo‐ 6‐thioxo‐6,7‐dihydro‐2H‐pyrazolo[3,4‐d]pyrimidin‐5(4H)‐yl)‐N‐ (4‐methylpyrimidin‐2‐yl)benzenesulfonamide (10b): Color: Yellow. Yield: 65%. M.p.: 138‐140 °C. FT‐IR (KBr, , cm‐1): 3160 (NH), 2880 (Str. CH3), 1690, 1660 (C=O), 1520 (C=N), 1480 (Defom. CH3), 1365 (NCSN), 1320 (SO2NH), 1255 (C‐F), 1190 (C=S), 880 (Aryl CH), 710 (C‐Cl), 680 (C‐F). MS (EI, m/z (%)): 722.76 (59). UV/Vis (EtOH, λmax, nm, (ɛ)): 308 (1.11). Anal. calcd. for C35H23ClFN7O4S2: C, 58.05; H, 3.20; N, 13.54; S, 8.86. Found: C, 57.85; H, 2.99; N, 13.31; S, 8.55%. 2.2.10. Synthesis of compounds 11 A mixture of 4‐fluoroaniline (0.001 mol) and benzoyl isothiocyanate (0.001 mol) in THF (20 mL) was refluxed for 1 h, cooled. The solid product was filtered off and crystallized from dioxan to give compound 11 as greenish yellow crystals (Scheme 3). N‐((4‐Fluorophenyl)carbamothioyl)benzamide (11): Color: Greenish yellow. Yield: 88%. M.p.: 94‐96 °C. FT‐IR (KBr, , cm‐ 1): 3230, 3150 (NH, NH), 1680, 1660 (C=O), 1504 (C=N), 1385 (NCSN), 1152 (C=S), 864, 808, 719 (Aryl CH), 657 (C‐F). 1H NMR (400 MHz, CDCl3, δ, ppm): 4.23 (s, 1H, NH), 7.00‐8.01 (m, 9H, Ar‐H), 8.70 (s, 1H, NH). 13C NMR (100 MHz, CDCl3, δ, ppm): 176.79, 168.19, 161.44, 159.86, 133.86, 131.81, 128.77, 128.73, 128.69, 128.21, 126.57, 126.52, 126.48, 126.43, 115.61, 115.46, 77.83‐77.41, 40.41‐39.46. MS (EI, m/z (%)): 274.03 (100). UV/Vis (EtOH, λmax, nm, (ɛ)): 265 (1.700). Anal. calcd. for C14H11FN2OS: C, 61.30; H, 4.04; N, 10.21; S, 11.69. Found: C, 61.01; H, 4.00; N, 9.82; S, 11.44%. 68 Al‐Harbi et al. / European Journal of Chemistry 6 (1) (2015) 63‐70 2.2.11. Synthesis of compounds 12 A mixture of compound 11 (0.001 mol) and malonic acid (0.001 mol) in a few drops of acetyl chloride and glacial acetic (20 ml) was refluxed for 2 h, cooled and poured onto ice. The solid product was filtered off and crystallized from 1,4‐dioxan to give compound 12 as yellowish crystals (Scheme 3). 1‐Benzoyl‐3‐(4‐fluorophenyl)‐2‐thioxodihydropyrimidine‐4, 6(1H,5H)‐dione (12): Color: Yellowish. Yield: 80%. M.p.: 170‐ 171 °C. FT‐IR (KBr, , cm‐1): 3539 (OH), 1680, 1660 (C=O), 1506 (Deform. CH2), 1438 (Deform. CH2), 1385 (NCSN), 1255 (C‐F), 1211 (C=S), 864, 840, 772, 710 (Aryl CH), 658 (C‐F). MS (EI, m/z (%)): 341.59 (48). UV/Vis (EtOH, λmax, nm, (ɛ)): 288 (1.029). Anal. calcd. for C17H11FN2O3S: C, 59.64; H, 3.24; N, 8.18; S, 9.35. Found: C, 59.41; H, 3.10; N, 8.00; S, 9.13%. 2.2.12. Synthesis of compounds 13 A mixture of compound 12 (0.001 mol) and methyl 2‐ chloromalonate (0.001 mol) in dry toluene (20 mL) with a few drops of triethylamine (TEA) was refluxed for 1h, cooled and addition the pet‐ether 80‐100 °C. The solid product was filtered off and crystallized from 1,4‐dioxan to give compound 13 as yellowish crystals (Scheme 3). Dimethyl 2‐(1‐benzoyl‐3‐(4‐fluorophenyl)‐4, 6‐dioxo‐2‐ thioxohexahydropyrimidin‐5‐yl)malonate (13): Color: Yellow. Yield: 65%. M.p.: 144‐146 °C. FT‐IR (KBr, , cm‐1): 3550 (OH), 3080 (aryl CH), 2950, 2880 (aliphatic CH), 1700, 1680, 1660 (C=O), 1506, 1438 (deform. CH2), 1385 (NCSN), 1255 (C‐F), 1211 (C=S), 1090 (C‐O‐R), 864, 840, 772, (aryl CH), 658 (C‐F). 1H NMR (400 MHz, CD3Cl, δ, ppm): 1.39‐1.37 (m, 6H, 2CH3), 2.59‐2.58 (m, 2H, CH of malonate and thiobarbituric acid), 7.01‐7.97 (m, 9H, Ar‐H), 9.80 (s, 1H, OH). 13C NMR (100 MHz, CDCl3, δ, ppm): 166.32, 159.79, 158.18, 135.15, 135.07, 131.45, 128.30, 127.69, 122.40, 122.35 115.20, 115.05. 77.74‐77.36, 45.87, 40.44‐39.49. MS (EI, m/z (%)): 472 (100). UV/Vis (EtOH, λmax, nm, (ɛ)): 268 (1.311). Anal. calcd. for C22H17FN2O7S: C, 55.93; H, 3.63; N, 5.93; S, 6.79 %. Found: C, 55.79; H, 3.50; N, 5.77; S, 6.45%. 2.2.13. Synthesis of compounds 14 Equimolar amounts (0.01 mol) of compounds 11 and 13 was refluxed in dry 1,4‐dioxan (50 mL) for 4h and cooled. The solid product was filtered off and crystallized from 1,4‐dioxan to give a white crystal (Scheme 3). 1,1'‐Dibenzoyl‐3, 3'‐bis(4‐fluorophenyl)‐2, 2'‐dithioxotetra hydro‐[5, 5'‐bipyrimidine]‐4, 4', 6, 6'(1H, 1'H, 5H, 5'H)‐tetraone (14): Color: White. Yield: 70%. M.p.: 124‐126 °C. FT‐IR (KBr, , cm‐1): 3528 (OH), 1700, 1680, 1661 (C=O), 1385 (NCSN), 1255 (C‐F), 1180 (C=S), 864 (Aryl CH), 658 (C‐F). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.589‐2.583 (m, 2H, 2CH), 7.01‐7.97 (m, 18H, Ar‐H), 9.84 (s, 1H, OH), 11.32 (s, 1H, OH). 13C NMR (100 MHz, CDCl3, δ, ppm): 166.31, 159.76, 158.16, 135.12, 135.10, 131.44, 128.29, 128.23, 127.69, 126.60 122.39, 122.35 115.97, 115.82. 115.17, 115.03, 77.84, 45.85, 40.32. MS (EI, m/z (%)): 684 (M+2, 3.53). UV/Vis (EtOH, λmax, nm, (ɛ)): 282 (0.2011). Anal. calcd. for C34H20F2N4O6S2: C, 59.82; H, 2.95; N, 8.21; S, 9.39. Found: C, 59.77; H, 2.90; N, 7.99; S, 9.28%. 3. Results and discussion 3.1. Chemistry Thiobarbituric acids have activated tautomers, and the CH2 at position‐5 is an active site for addition, alkylation, acylation and also condensation reactions [9,28,29]. Thus, careful addition of 4‐fluoroaniline to aryl isothiocyanates in warmed THF produced compound 1a‐c. Heterocyclization of compounds 1a‐c by reflux with malonic acid in the presence of acetyl chloride‐acetic acid mixture, yielded compounds 2a‐c. Addition of compounds 2a to cyclohexyl isocyanate in warmed ethanol‐piperidine furnished compound 3 (Scheme 1). Forma‐ tion of compound 3 took place by a nucleophilic attack of CH2 at position‐5 of compound 2a with a more electrophilic carbon of isocyanate. Structures of compounds 1‐3 were characterized from correlated elemental analysis and spectral data. The IR spectrum of compound 1a recorded absorption band at 3180 cm‐1 attributed to presence of NH functional groups, which lacks in compound 2a. Compounds 2a‐b and 3 showed an absorption bands at 1680, 1668 and at 2856, 1488 cm‐1 due to the presence of both two carbons and active methylene. Only, the spectrum of compound 3 showed the third C=O and one NH functional group at 1668 and 3180 cm‐1. The 1H NMR spectrum of compound 2a display doublets at δ 2.59‐2.58 (s, 2H, CH2) ppm due to active ethylene at 5‐positions. 13C NMR of both compound 2a showed a resonated signal at 166.32 and 158.17 ppm for C=O and C=S carbons with resonated =CH at δ 40.43 ppm. Compound 2a exhibited m/z at 314 as base peak. UV spectra of compound 3 are more than compound 2 at λmax (275 and 258 nm) attributed to heteroconjugation systems formed. It is interest that, compounds 2 and 3 showed a violet color with FeCl3 solution which confirm that these systems exist as enolic form rather than ketonic formula. Reflux compound 3 with glacial acetic acid in a fused sodium acetate yielded compound 4. Polyfunctional pyrimidopyrimidines use as multi‐targeted small molecule inhibitors and resistance modifying agents [30,31]. Similary, cycloaddition of substituted thiourea 1 with compound 3 in methanolic NaOH produced compounds 5 and 6 (Scheme 1). Structures of compounds 4‐6 deduced from their correct elemental analysis and spectral measurements. IR spectra of compound 5 and 6 showed  at 3150‐3123 cm‐1 attributed to exo ‐NH‐ while that lacks in compound 4. 1H NMR spectra of compound 6 recorded signal at δ 11.55 ppm for NH protons. 13C NMR spectra of compounds 6 showed δ at 207.02 and 157.10 ppm for C=S, and C=O appeared for compound 4. UV absorption spectrum of compound 6 exhibited λmax at 287 nm which higher than compound 3, which is due to more conjugation system. Compound 4 showed a molecular ion and a base peak at m/z 422. Addition sulfa drugs as primary aromatic amines to benzoyl isothiocyanates in warm THF, produced compound 7a‐c. Heterocyclization of compound 7 with malonic acid in warm acetyl chloride‐acetic acid produce compounds 8a‐c. Which contain active CH2 at position‐5. Treatment of compounds 8a, b with 4‐fluorobenzoyl chloride in warm DMF yielded compound 9. Ring closure reaction of compound 9 with 4‐chlorophenyl hydrazine in reflux absolute ethanol afforded compound 10a, b (Scheme 2). The former structure of compounds 7‐10 have been established from their corrected elemental analysis and spectral data. IR spectra showed an absorption band at 3500‐ 3150 and 1580 cm‐1 for (HO‐C=N ⇄ CO‐NH) for compound 7a‐ c. Also, compound 9 recorded a multi‐absorption bands at 1680‐1660 cm‐1 attributed to four C=O functional groups. Only the compound 10b recorded an absorption band for C=N at 1520 cm‐1. All the IR spectra of compounds 7‐10 showed an absorption band at  for the acidic ‐NHSO2‐ group. 1H NMR spectra of compound 8a recorded a resonated signal at δ 2.60‐ 2.21 ppm for active CH2 at position‐5. In addition 13C NMR spectrum of compound 8a showed a resonated signal at δ 179.26, 173.06 and 169.22 ppm attributed to C=S and C=O carbons with δ 40.42‐39.47 ppm for CH2. M+/S of compound 8a recorded a base peak at m/z 485.94. UV absorption spectrum of compound 10a exhibited λmax at 315 nm higher than compounds 9, 8 and 7 (λ at 294, 280 and 238 nm. Mass of compound 10b showed a molecular ion of M‐24 with a base peak at 722 m/z. Compound 7 showed a violet color when treated with FeCl3 solution, which confirm that enolic structure than ketonic formula (enolization preferred towards aryl groups). Al‐Harbi et al. / European Journal of Chemistry 6 (1) (2015) 63‐70 69 Table 1. Anti‐HIV activity data of the thiobarbituric acids *. Compound IC50 (µM) EC50 (µM) CC50 (µM) SI Present of protection Present of infected 2 9.3±1.5 48±1.7 87.0±3.8 1.81 4.90 7.15 8a 4.5±0.2 31±1.1 60.0±5.5 19.35 7.95 9.88 8b 4.6±0.8 2.3±0.5 48.8±81 21.21 7.55 10.30 8c 3.1±0.5 6.6±0.8 41.01±40 6.21 12.15 13.55 9a 3.2±0.6 24.08 2.8 75.0±1.0 3.12 10.70 11.51 12 7.7±0.1 6.8±0.8 36±2.6 5.29 5.88 7.90 14 2.7±0.1 13.8±1.8 28.5±1.3 2.06 16.01 15.11 * IC50: The half maximal inhibitory concentration is a measure of the effectiveness of a compound in inhibiting biological or biochemical function; EC50: The term half maximal effective concentration refers to the concentration of a drug, an antibody or toxicant which induces a response halfway between the baseline and maximum after a specified exposure time; CC50: Cytotoxicity concentration; SI: Selectivity Index CC50/EC50. Similarly, the addition of 4‐fluoroaniline to benzoyl isothiocyanate in warm THF produce compound 11. Heterocyclization of compound 11 by refluxing with malonic acid in acetyl chloride‐acetic acid [32] yielded compound 12 (Scheme 3). It is interest that a simple alkylation of α‐active proton of compound 12 via nucleophilic attack to labile chloride atom containing α‐keto‐alkylating agents [33,34]. Alkylation of compound 12 by using dimethyl 2‐chloro malonate in boiling dry toluene in the presence of drops triethylamine, compound 13 isolated. Full hetero‐cyclization of compound 13 by reaction with compound 11 in reflux THF, afforded the bis‐compound 14 (Scheme 3). Former structures of compound 11‐14 have been deduced from the corrected elemental analysis and spectral data. IR spectrum of compound 11 recorded the absorption band at 3230‐3150 cm‐ 1 due to CONH ⇄ HO‐C=N, in addition at 1385 cm‐1 for NCSN. On the other hand IR spectra of compounds 12‐14 showed absorption bands at  1680, 1660 cm‐1 attributed to 1,3‐ dicarbonyl groups with characteristic bands at  1211 and 1180 cm‐1 for C=S groups and 1255 cm‐1 for C‐F. 13C NMR spectrum of compound 14 showed a resonated signals at 166.31 and 159.76 ppm attributed to C=S and C=O carbons, in addition at δ 131.41‐122.35 and 45.85, 40.32 ppm for aromatic and aliphatic carbons. UV absorption spectra of compounds 11‐14 give us indication about the ring closure reactions of compound 11 to 13 and 14. Compound 11 showed λmax at 265 nm, compound 12 at 288 and compound 14 at 282 nm. These data confirm that formation of heterocyclic systems from compounds 11 to 12. Mass of compound 14 exhibited a molecular ion and the base peaks at m/z 684 (M+2) and 685 (M+3). 3.2. Pharmacological Evaluation Recently, thiobarbituric acid derivatives proved to be virus inhibitors, especially hepatitis’s C virus (HCV) NS5B polymerase. Besides, they suppressed the synthesis of RNA by recombinant HCV NS5B polymerase dependent manner [35‐ 39]. The prominent role of fluorine substituent on bioactivity is due to the effect C‐H acidity which depends on several factors, including the site of fluorination and the geometry of the conjugate carbon ion. Based on these observations, The present work depends on the synthesis of fluorine substituted thiobarbituric acid derivatives and their related heterocyclic systems and their evaluation as potential inhibitors, especially HIV‐1 and inhibition of cyclin‐dependent kinase 2 (CDK2) for tumor cell. 3.2.1. Anti‐HIV‐1 Testing All the new synthesized compounds evaluated for their in vitro anti‐ HIV activities were performed on T‐4 Lymphocytes uninfected or infected with HIV‐1 using DMSO as solvent. The assay basically involves the killing T‐4 Lymphocytes by HIV. Compounds that degenerate or are rapidly metabolized in the culture conditions may not show activity in this screening. The viability of the cells was determined spectrophotometrically using the tetrazolium assay procedure. The concentration was tested range 1×10‐4 to 1×10‐8 M and determined GI50, TGI and LC50 values. The arrangements of atoms across the skeleton, concepts of steric relations and molecular bulk branched ness and relationships among various non‐branched parts of the molecule are considered in these methods. Thus, we report here the correlation of cytotoxicity and anti‐HIV activity of fluorinated thiobarbituric acid derivatives in view to provide a better rational approach for the design of potent drugs. The electronic parameter (equalized electronegativity) hydro‐ phobic parameter and steric parameter of the tested systems synthesized give us a good indication about the role of electronic nature, hydrophobicity, and molecular size of the fluorinated thiobarbituric acid derivatives molecules on the activity. HIV‐1 envelope glycoprotein (Env) transmembrane submit glycoprotein 41 (gp41) plays a crucial role in mediating virus, fusion and entry. When the human immunodeficiency virus (HIV) fuses to the host cell, the N‐ terminal heptads repeat (NHR) and C‐terminal heptads repeat (CHR) of gp41 interact to form a six‐helix bundles (6‐HB) core structure, bringing the viral and host cell membranes into sufficient proximity to allow fusion. The fluorinated thiobarbituric acid derivatives synthesized were evaluated as anti‐HIV and the results were obtained reported in Table 1 [40]. From the data obtained it can be concluded that the order of activity of these targets is 14 > 8c > 9a > 8a > 8b > 12 > 2. The most activity compounds 14, 8c, 9a and 8a which are due to the presence of fluorine substituted thiobarbituric acids. These active compounds exhibited significant potency against gp41 6‐HB formation with IC50 values of 4.5 and 4.6 µM and against HIV‐1 replication in the MT‐2 cells with EC50 values of 3.1 and 3.2 µM, respectively. Thus, providing a new starting point to develop highly potent small molecule HIV fusion inhibitors targeting gp41. On the other hand, compounds 14, 8c, 9a and 8a recorded a higher percent of protection (Table 1). 3.2.2. Inhibition of cyclin‐dependent kinase2 (CDK2) for cell‐tumor division Various thiobarbituric acid derivatives exhibited anticancer activities [40,41]. A recent control on the cell tumor division depends on the use of polyfunctional heterocyclic nitrogen systems for inhibition of cyclin‐dependent kinase 2 (CDK2) as tyrosine kinase inhibitors [42]. Thus, the present work aimed to prepare of new fluorine substituted thiobarbituric acid derivatives and their heterobicyclic nitrogen systems as a novel scaffold for the development of antiproliferative agents with possible pharmacological applications in oncology. The synthesized compounds were evaluated for their ability to inhibit acidity of CDK2 in a biochemical assay [43] with IC50 values comparable to olomoucine as standard according to the reported methods. The obtained data were reported in Table 2. In view of the results obtained, the most active compounds bear a fluorine atom followed by a sulfa‐drug moiety. In addition, we observed that a 4‐fluorophenyl side chain at position 1 or 3 significantly decreases CDK2 inhibitory acidity. The activity of 70 Al‐Harbi et al. / European Journal of Chemistry 6 (1) (2015) 63‐70 the tested targets as 12 > 14 > 2 > 9a > 8a > 8b > 8c in comparing with olomoucine as standard. Table 2. Results CDK2 inhibition tests (IC50 in µmol/dm) *. Compound IC50 CDK2±SD (µM) 2 11.0±4.5 8a 15.1±5.3 8b 17.4±3.8 8c >20 9a 14.1±1.8 12 4.5±2.8 14 5.2±1.73 Olomoucine 5.0±1.0 * SD: Standard deviation, Olomoucine value is included as a control. 4. Conclusion Simple routs were explored to synthesize new fluorinated fused heterobicyclic systems containing a thiobarbituric acid moiety starting with fluorinated N,Nʹ‐diarylthiobarbituric acid, 2. Some of new synthesized systems recorded good anti HIV‐1 and cyclin dependent kinase 2. We hope that this approach may be a value to others seeking novel synthetic fragments with unique properties for medicinal chemistry. Acknowledgements I would also like to extend my sincere thanks and appreciations to all technical staff members at National Cancer Institute USA for valuable medical evaluation. Also, my thanks to all technical staff members at Chemistry Labs (UV, IR, NMR) spectra. References [1]. Abdel‐Rahman, R. M. Pharmazie 2001, 56, 18‐22. [2]. DeClercq, E. Biochi. Biophys. 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