Organophosphorus systems are ubiquitous in nature and exhibit many applications in the field of agriculture medicine and industry [1] [2] . Many multi-ring phosphorus heterocycles are used as pesticide [3] , bactericide [4] -[6] , antibiotics [4] , and acts as HIV protease inhibitors [7] . Thus, synthesis of new phosphorus bearing a heterocycles has attracted the attention of researchers. Phosphorylation of organic compounds often improves their biological activity, especially through a vital energy, because the P-O is the store of energy for metabolism process. For example, phophorylated-N in the nucleocapsid affects the interaction between the N-atom and the genomic RNA. The charge repulsion between the negatively charged phosphoserine and the negatively charged RNA may weaken the interaction between N-atom and RNA, thus enabling the viral polymerase to gain access to genomic RNA and to initiate viral RNA transcription and replication [8] . On the other hand, chemistry of N-phosphorylheterocycles showed that these compounds from two dimensional polymeric chains via intermolecular P-O⁻⁺H-N hydrogen bonds [9] . Also, phosphodiester compound had a type of action, especially enzymetic of DNA replication [10] on DNA ligase as (Figure 1(.

It is interesting that fluorine containing aheterocycles bearing functional groups exhibits highly effective in biological process, pharmaceuticals, agrochemicals, polymers and a wide range of consumer products [11] . It reflects its resistance to metabolic change due to the strength of the C-F bond providing biological stability and the application of its nonstick-interfacial physical characteristics [12] -[16] . Abdel-Rahman et al. [17] -[21] reported the synthesis and chemical reactivity of 3-thioxo-1,2,4-triazin-5 one derivatives as a bioactive molecules, especially as anti-cancer, anti-AIDS, Amyllolytic, cellobiase and antimicrobial agents. Based upon these observations, the aim of this work is to study the formation of 6-(5’-fluoro-2’-phosphoryl anilido-3-hydrazino-1,2,4- triazin-5 (2H) one then study their behaviour as electron donor towards different electron acceptors such as carbo-sulfur, oxygen, halogen and nitrogen compounds; finally, a type of isolated and/or fused heterobicyclic systems obtained and evaluation as potential inhibitors towards HIV-1 virus.

Melting points were determined with an electro-thermal Bibbly Stuart Scientific Melting point SMPI (UK). A perkin Elmer (Lambda EZ-2101) double beam spectrophotometer (190 - 1100 nm) used for recording the electronic spectra. A Perkin Elmer model RXI-FT-IR 55,529 cm⁻¹ used for recording the IR spectra (EtOH as solvents). A Brucker advance DPX 400 MHz using TMS as an internal standard for recording the ¹H/¹³C NMR spectra in deuterated DMSO (δ in pp m). AGC- MS-QP 1000 Ex model is used for recording the mass spectra. Hexafluorobenzene was used as external standard for ¹⁹FNMR at 84.25 MHz and ³¹P (in CDCl₃, 101.25 MHZ).

Elemental analysis was performed on Micro analytical Center of National Reaches Center-Dokki, Cairo, Egypt. Compound 1 prepared according the reported method [17] .

6-(2’-aminos-5’-fluorophenyl-3-thioxo-1,2,4-triazin-5(2H)one (1)

A mixture of 5-fluoroisatin (0.01 mol) in sodium hydroxide solution (5%, 50 ml) warm for 10 min, then thiosemicarbazide (0.01 mol, in hot water, 10 ml) add and complete the refluxing for 2 h. The reaction mixture cooled then poured onto ice and neutralize with diluted HCl. The solid thus obtained filtered off and crystallized from ethanol to give 1 as yellow crystals, yield 80%; m.p. 265˚C. Analytical data; found: C, 44.91; H, 2.90; F, 7.58: N, 23.40; S, 13.29%.Calculated for C₉H₇FN₄OS (238); C, 45.37; H, 2.94; F, 7.98; N, 23.52; S, 13.44%.UV: λ_max (EtOH) = 280 nm. IR νcm⁻¹: 3424(NH₂), 3258, 3169 (NH, NH), 1685 (C=O), 1618 (deform. NH₂), 1545 (C=N), 1263 (C-F), 858,818 (aryl CH), 685 (C-F). ¹H NMR (DMSO) δ = 14.66, 12.66, 10.90 (each s, 1H, 3NH), 8.68 - 8.06, 7.69 - 7.64, 7.39 - 7.30, (s, 3H, aryl protons). ¹³C NMR (DMSO): δ 179.47(C=S), 162 (C=O), 159 - 157 (C-F), 138.54 (C=N), 131.82, 121.8, 121.51 (aromatic carbons, 78.14, 77.71 (C₅ - C₆, 1,2,4-trinzine). M/Z (Int. %); 256 (M + H₂O, 5%), 68 (100), 148(21), 138(18), 110 (30), 96 (50), 82(58.0), 70(78).

6-(5’-Fluoro-2’-diphenylphosphorylanilido)-3-thioxo-1,2,4-triazin-5(2H)one (2)

Equimolar mixture of compound 1 and diphenylphosphoryl chloride in DMF (20 ml) warm for 1h, cooled then poured onto ice. The produce solid filter off and crystallized from methanol to give 2 as deep yellow crystals. Yield 70%; m.p. 218-220˚C. Analytical data; found: C, 53.39; H, 3.51; F, 3.88: N, 11.69%.Calculated for C₂₁H₁₆FN₄PSO₄(470); C, 53.61; H, 3.70; F, 4.04; N, 11.91%. IR νcm⁻¹: 3133.8 (NH), 1688.4 (C=O), 1574 (C=N), 1370 (Cyclic NCSN), 1262 (C-F), 1200 (P=O), 1150 (C-S), 10.96 (Ph-O-P), 858, 801 (substituted phenyls) M/Z: (Int.%); 473 (M + 3, 5.11), 110 (100).

3-Hydrazino-6-(5’-fluoro-2’-diphenylphosphorylanilido)-1,2,4-triazin-5(2H)one (3)

A mixture of compound 2 (1 gm) and hydrazine hydrate (2ml) in ethanol (50ml) reflux for 2h. cooled. The solid thus produce filter off and crystallized from ethanol to give 3 as orange crystals, yield 85%; m.p. 178˚C - 180˚C. Analytical data; found: C, 53.45; H, 3.59; F, 3.80%.Calculated for C₂₁H₁₈FN₆PO₄(468), C, 53.84; H, 3.84; F, 4.02; N, 17.14%. IR ν cm⁻¹ = 3381, 3340, 3220 - 3190 (NH, NH, NH₂), 1682 (C=O), 1558 (C=N), 1266.9 (C-F), 1210-1156 (P=O). 1050 (Ph-O-P), 860,805 (substituted phenyls).¹H NMR(DMSO) δ = 10.7, 10.2, 8.7 (each s, 3H, 3NH, 1,2,4-triazino NH-P=O), 7.511, 7.27-2.24, 7.23-7.22 (each s, 3H, aryl protons); 7.143 - 7.002; 6.860 - 6.796 (each m, 10H, phenyl protons), 2.88 (s, 2H, NH₂ of hydrazine), ¹³C NMR (DMSO) δ = 163.78, 159.44, 157.86, 134.97, 129.07, 127.65, 123.66, 122.87, 120.12, 120.09, 113.47, 113.31, 110.77, 110.71, 107.93, 105.27, 105.10, 77.76, 77.33.

3-(3’-Amino-4’-carboxy-5-(4-chlorophenyl)-4’,5’-dihydro-pyrazolin-1’-yl)-6-(5’-fluoro-2’-diphenylphosph- orylanilido)-1,2,4-triazin-5(2H)one (4)

Equimolar amounts of 3 and α-(4-chlorophenylidene) cyano acetic acid in ethanol (100 ml) and a few drops piperidine (0.5 ml) reflux for 8h, cooled, then added off and crystallized from dioxan to give 4 as yellowish crystals, yield 65% m.p., 158˚C - 160˚C. Analytical data; found: C, 54.81; H, 3.11; F, 2.55; Cl, 5.09; N, 14.29%. Calculated for C₃₁H₂₄FClN₇PO₆(675). C, 55.11; H, 3.55; F, 2.81; Cl, 5.18; N, 14.51%; M/S: 675 (1.11), 95(100). IR νcm⁻¹: 3420 (OH), 3381, 3155 (NH, NH₂), 1680 (C=O) 1558(C=N), 1478 (deform aliphatic CH), 1269 (C-F), 1200 (P=O), 1043 (Ph-O-P), 993.861, 804 (Aryl CH).¹H NMR (DMSO) δ = 10.67, 10.14, 8.72 (each δ, 3H, 3NH, 1,2,4-triazinare NH-P=O), 9.77 (δ, 1H, OH), 8.15 - 7.52, 7.36 - 7.29, 7.13 - 7.00, 6.991 - 6.811 (each m, 19H, 7H aryl, 10H phenyls pyrazole protons); 3.46 (δ, 2H, NH₂).¹³C NMR (DMSO) δ: 179.64; 163.76; 163.05; 159.42; 157.84; 138.58; 134.94; 128.65; 127.59; 123.72; 123.66; 121.13; 121.07; 117.67; 117.51; 113.45; 113.28; 112.06; 112.01; 110.75; 110.70; 109.66; 108.09; 107.92; 105.25; 105.08; 77.78; 77.35; 23.64.

3-(3’-Methyl-5’-arylamino-pyrazolin-1’-yl)-6(5’-fluoro-2’-diphenylphosphorylanilido)-1,2,4-trinzin-5(2H) one (5)

A mixture of 3 (0.01 mol) and acetyl acetanilide derivative (0.01 mol) in DMF (50 ml) reflux for 2h, cooled then poured onto ice. The solid thus yield filtere off and crystallized from dioxan to give 5 as deep-yellowish crystals, yield 70%; m.p. 100˚C - 101˚C. Analytical data; found C, 56.03; H, 3.41; F, 2.23; N, 16.17; S, 3.91%. Calculated for C₃₆H₂₉FN₉PSO₆(765). C, 56.47; H, 3.79; F, 2.48; N, 16.47; S, 4.18%. IR νcm⁻¹: 3424, 3220 - 31.70 (NH, NH), 2932 (CH₃), 1694 (C=O), 1620 (C=N), 1358 (SO₂-NH), 1268 (C-F), 1220 (P=O), 1054 (Ph-O-P), 952, 909, 810, 758 (aryl CH).¹H NMR (DMSO) δ = 12.28, 12.27, 10.36, 10.21 (each s, 4H, 4NH) 9.7 (s, 1H, C₄- of pyrazole), 7.979, 7.971, 7.556, 7.545 (m, 4-H of pyridine); 7.34, 7.336, 7.322, 7.091(m, 4H of aryl-P-SO₂NH) 6.95 - 6.83; 6.66 - 6.52; 6.41 - 6.16 (each m, 13H of FC₆H₃, 2C₆H₅). 0.46 - 0.45 (s, 3H, CH₃). ¹³C NMR(DMSO) δ = 179.64, 163.75, 163.03, 162.41, 158.08, 157.99, 157.47; 151.97; 138.58, 134.94, 130.23, 129.10, 123.72, 123.66, 117.66, 117.50, 115.11, 113.41, 113.25, 112.97, 112.07, 112.02, 110.76, 110.71, 108.09, 107.92, 105.21, 105.04, 77.83-77.40, 36.40, 31.29.

3-(3’-Amino-4’,5’-dihydro-5’-oxo-pyrazolin-1’-yl)-6(5’-fluoro-2’-diphenylphosphorylanilido)-1,2,4-triazin- 5(2H)one (6)

Equiomolar of 3 and ethyl cyanoacetate in THF (100ml) reflux for 4H, cooled. The solid thus produce filtered off and crystallized from THF to give 6 as faint yellow crystals, yield 68%; m.p. 200-202˚C. Analytical data; found: C, 53.53; H, 3.31; F, 3.29; N, 18.01%. Calculated for C₂₄H₁₉FN₇PO₅(535); C, 53.83; H, 3.55; F, 3.55; N, 18.31%. IR νcm⁻¹: 3425 (NH₂), 3220-3190 (NH OH), 1694 (C=O), 1471 (deformation. CH₂), 1310 (N-N), 1250 (C-F), 1210 (P=O), 1058 (Ph-O-P), 952, 915, 808 (aryl CH).¹H NMR (DMSO) δ: 12.7, 10.67, 8.8 (each s, 3H, 3NH), 10.24 (s, 1H, OH of pyrazole), 7.66 - 7.400, 7.39-7.00, 6.99-6.79 (each m, 14H, aryl & phenyl protons). ¹³C NMR(DMSO) δ:179.54, 163.70, 159.31, 157.74, 134.91, 128.98, 127.31, 123.68, 117.57, 113.29, 113.13, 111.95, 110.69, 110.64, 108.23, 105.08, 104.91, 78.0-77.54.

3-(3’,5’-Diaminopyrazolin-1’-yl)-6-(5’-fluoro-2’-diphenylphosphorylanilido)-1,2,4-triazin-5(2H)one (7)

A mixture of 3 (0.01mol) and malononitrile (0.01 mol) in ethanol (50ml) and piperidine (0.5 ml) reflux for 8h, cooled. The solid obtained filtered off and crystallized from ethanol to give 7 as deep orange crystals. Yield 70%; m.p. 205˚C - 207˚C. Analytical data; found: C, 53.55, H, 3.12; F, 3.31; N, 20.71%. Calculated for C₂₄H₂₁FN₈PO₄ (535); C, 53.83; H, 3.55; F, 3.55; N, 20.93%. IR: νcm⁻¹ 3430 - 3380 (NH₂), 1700 (C=O), 1620 (deform. NH₂), 1580 (C=N) 1265 (C-F), 1200 (Ph-P=O), 1050 (Ph-O-P), 930, 910, 850, 800(aryl CH).¹H NMR (DMSO) δ: 12.7, 10.7, 10.2 (each s, 3H, 3NH), 8.8 (s, 1H, NH-P=O), 7.55 - 7.311, 7.131 - 6.991, 6.87 - 6.76 (each m, 14 H, aryl & phenyl protons), 3.89 (s, 4H, 2NH₂). ¹³C NMR (DMSO)δ: 163.73, 159.38, 157.80, 134.93, 127.49, 123.67, 113.38, 113.22, 110.66, 105.18; 105.01, 77.84-77.41, M/S (Int.%): 534 (536, M + 2, 1.55%), 248 (1.11), 97 (3.18) 96 (5.55), 95 (100), 93 (18.11), 68 (42.00), 67 (3.11), 62 (37.15).

3-(5’-Phenyl-3’-oxo-2,3,4,5-tetrahydro-pyrazolin-1’-yl)-6-(5’-fluoro-2’-diphenyl phosphorylanilido)-1,2, 4-triazin-5-(2H)one(8)

Equimolar amounts of 3 and cinnamoyl chloride in DMF (20ml) reflux for 4 h, cooled then poured onto ice. The produce solid filtered off and crystallized from dioxan to give 8 as deep yellowish crystals, yield 60%, m.p. 160˚C_. - 162˚C_. Analytical data; found: C, 59.89; H, 3.55; F, 3.01; N, 13.75%. Calculated for C₃₀H₂₃FN₆PO₅ (597); C, 60.30; H, 3.85; F, 3.18; N, 14.07%. IR νcm⁻¹: 3428 (OH), 3180 (NH), 2937 (CH₂), 1694 (C=0), 1610 (C=N), 1482 (deform. CH₂), 1314 (N-N), 1230 (C-F), 1169 (P=O), 1059 (Ph-O-P), 954, 909, 809 (aryl CH).¹H NMR (DMSO) δ: 14.7, 13.5, 12.6 (each s, 3H, 3NH), 10.80 (s, 1H, OH of pyrazole), 8.8 (s, 1H, NH-P=O), 7.99 - 7.41, 7.04 - 7.32, 7.10 - 6.93, 6.88 - 6.40 (each m, 20H, aryl and phenyl protons), 3.23 (s, 2H, NH₂). ¹³C NMR (DMSO) δ: 163.70, 163.58, 162.90, 162.24, 159.34, 157.83, 157.76, 144.07, 134.29, 130.01, 128.77, 127.84, 121.16, 118.94, 118.84, 117.43, 114.23, 113.13, 112.97, 111.94, 111.89, 111.48, 111.43, 110.64, 110.59, 108.30, 108.12, 78.13 - 77.91, 36.26, 31.14.

3-(3’-(4’’-Nitrophenyl)-5’-(4’’-fluorophenyl)-4’-5’-dihydro-pyrazolin-1’-yl)-6-(5’-fluoro-2’-diphenyl-p- hos-phorylanilido)-1,2,4-triazin-5(2H)one (9)

A mixture of 3 (0.01 mol) and a chalcone (0.01 mol) in ethanol (50 ml), and piperidine (0.5 ml) reflux for 8 h, cooled then poured on ice-HCl. The solid produce filtered off and crystallized from THF to give 9 as yellow crystals, yield 82%, m.p. 148˚C - 150˚C. Analytical data; found: C, 59.49; H, 3.51; F, 5.21; N, 13.29%. Calculated for C₃₆H₂₆F₂N₇PO₆ (721); C, 59.91; H, 3.60; F, 5.27; N, 13.59%. IR νcm⁻¹: 3180 (NH), 2827 (CH₂), 1675 (C=O), 1595 (C=N), 1547 (C=N), 1500, 1423 (deform. CH₂), 1291 (C-F), 1225 (Ph-P=O), 1097 (Ph-O-P), 921, 847, 762 (aryl CH), 684 (C-Cl). ¹H NMR (DMSO) δ = 10.57, 10.115 (each s, 2H, 2NH), 8.160 - 8.157, (s, 1H, NH-P=O), 8.118 - 8.095, 7.838 - 7.49, 7.23 - 7.010, 6.92 - 6.90, 6.73 - 6.70 (each m, 23H, aryl & phenyl protons) 2.49 - 2.48 (δ, 2H_, CH₂). ¹³C NMR (DMSO) δ = 163.72, 159.35, 157.78, 134.92, 130.85, 130.80, 129.46, 127.41, 123.86, 123.73, 123.67, 121.10, 113.34, 113.18, 111.98, 110.72, 110.67, 108.09, 107.92, 105.13, 104.97, 77.92 - 77.50, 39.56.

3-(3’,5’-Dioxo-2’,3’,4’,5’-tetrahydro-pyrazolin-1’-yl)-6-(5’-fluoro-2’-diphenyl phosphorylanilido)-1,2,4- triazin-5’(2H)one (10)

Equimolar mixture of 3 and diethyl malonate in THF (100 ml) reflux for 8 h, cooled. The solid thus obtain filtered off and crystallized from dioxan to give 10 as faint yellow crystals, yield 66%, m.p. 189-190˚C. Analytical data; found: C, 53.35; H, 3.18; F, 3.35; N, 15.38%. Calculated for C₂₄H₁₈FN₆PO₆(536); C, 53.73; H, 3.35; F, 3.54; N, 15.67%. IR νcm⁻¹: 3300 (NH), 3169 (NH), 1694 (C=O), 1626 (C=N), 1579 (C=N), 1471 (deform. CH₂), 1304 (N-N), 1265 (C-F), 1196 (P=O), 1040 (Ph-O-P), 903, 863, 809 (aryl CH).¹H NMR (DMSO) δ = 12.7, 10.69, 10.35 (each s, 3H, NH, OH, OH) 9.21 (s, 1H, NH-P=O), 8.15 (s, 1H, C₄ of pyrazole), 7.79 - 7.38, 7.10 - 7.003, 6.99 - 6.79 (each m, 15H, aryl & phenyl protons), 4.18 - 4.17, (δ, CH₂ of pyrazole). ¹³CNMR (DMSO) δ = 179.39, 163.58, 162.91, 159.18, 157.61, 134.86, 126.95, 123.74, 123.68, 117.44, 117.28, 113.13, 112.97, 111.94, 110.64, 110.58, 108.12, 107.95, 104.89, 104.72, 78.29 - 77.85, 61.09, 13.94. M/S (Int.%): 536 (538, M + 2, 2.28), 99 (5.5), 96 (13.11), 95 (100), 93 (36.11), 69 (21.85), 68(42.35), 62(5.18).

3-(5’-Aryl-3’-thioxo-2’,3’-dihydro-1’,2’,4’-triazol-1’-yl)-6-(5’-fluoro-2’-diphenylphosphorylanilido)-1,2,4-triazin-5(2H) one (11)

A mixture of 3 (0.01 mol) and P-methoxybenzoylisothiocyanate (0.01 mol) in dioxan (20ml) reflux for 4 h, cooled. The solid produce filtered and crystallized from dioxan to give 11 as orange yellowish crystals. Yield 65%, m.p. 141˚C - 192˚C. Analytical data, found: C, 55.62; H, 3.41; F, 2.74; N, 15.02; S, 4.72%. Calculated for C₃₀H₂₃FNPSO₅ (643); C, 55.98; H, 3.57; F, 2.95; N, 15.24; S, 4.97%. IR νcm⁻¹ = 3220-3180 (b, NH), 1693 (C=O), 1624, 1537 (C=N), 1477 (deform. MeO), 1305(N-N), 1266(C-F), 1155 (C-S), 1099 (P=O), 1039(P-O), 980, 840, 809 (aryl CH). ¹H NMR(DMSO) δ = 12.74, 10.80 - 1066, 8.73 (each s, 3H, 3NH), 8.40 - 7.52, 7.38 - 7.30, 7.29 - 7.00, 6.99 - 6.800 (each m, 17H) aryl & phenyl protons), 3.68 - 3.67 (s, 3H, OMe). ¹³C NMR(DMSO) δ: 179.64, 163.77, 163.04, 159.40, 158.02, 157.85, 138.58, 134.94, 132.10, 127.60, 123.72, 123.66, 121.13, 121.07, 117.69, 117.53, 113.46, 113.28, 112.02, 110.76, 110.71, 108.10, 107.93, 105.25, 105.07, 77.81 - 77.35, 66.91.

3-(3’-(4’-Methoxyphenyl)-5’-thioxo-4’,5’-dihydro-1’2’,4’-triazol-1’-yl)-6-(5’-fluoro-2’-diphenylphos p-

horylanilido)-1,2,4-triazin-5(2H)one (12)

A mixture of 3 (0.01 mol) and 4-methoxybenzoyl isothiocynate (0.01 mol) is DMF (20 ml) reflux for 4 h, cooled then poured onto ice. The produce solid filtered off and crystallized from ethanol (to give 12 as orange crystals, yield 70%, m.p. 186˚C - 188˚C. Analytical data: found: C, 55.69; H, 3.55; F, 2.70; N, 14.89; S, 4.79%. Calculated for C₃₀H₂₃FN₇PSO₅ (643); C, 55.98; H, 3.57; F, 2.95; N, 15.24; S, 4.97%. IR νcm⁻¹: 3382 (NH), 3318 (NH), 3204 (NH), 1684 (C=O), 1562 (C=N), 1484 (deform. MeO), 1311 (N-N), 1270 (C-F), 1169 (C=S), 1041 (Ph-O-P), 995, 881, 807 (aryl CH).

3-Methyl-1H-7-(5’-fluoro-2’-diphenyl phosphorylanilido)-1,2,4-triazino[4,3-b][1,2,4] triazin-4,8-dione (13)

A mixture of 3 (0.01 mol) and sodium pyruvate (0.01 mol) in sodium hydroxide solution (5%, 100 ml) warm under reflux for 2 h, cooled them poured onto ice HCl. The solid thus obtained filtered off and crystallized 70%, m.p. 220˚C - 222˚C. Analytical data; found: C, 55.19; H, 3.31; F, 3.38; N, 15.88%. Calculated for C₂₄H₁₈FN₆PO₅ (520); C, 55.38; H, 3.46; F, 3.65; N, 15%. IR νcm⁻¹: 3380, 3162 (NH, NH) 1683 (C=O), 1589, 1553 (C=N), 1458 (deform. CH₃), 1308 (N-N), 1250 (C-F), 1204 (P=O), 1040 (Ph-O-P), 909, 861, 804 (aryl CH). ¹H NMR (DMSO) δ: 14.55, 12.8 (each s, 2H, 2NH), 10.06 (s, 1H, NH), 7.66 - 7.40, 7.35 - 7.26, 6.93 - 6.76 (each m, 13H, aryl & phenyl protons), 5.58 (s, 1H, OH), 1.256 (s, 3H, CH₃). ¹³C NMR(DMSO)δ:177.40, 176.13, 158.14, 139.40, 128.24, 119.11, 118.95, 118.82, 117.83, 114.59, 114.43, 114.35, 114.29, 112.36, 112.19, 112.09, 112.04, 111.84, 111.77, 111.60, 110.87, 109.95, 109.90, 108.90, 108.37, 77.67 - 77.24, 55.38, 17.21.

Indolo[3,4-e][1,2,4] triazino [4,3-b]-1,2,4-triazin-11-one (14)

Equimolar amounts of 3 and isatin in DMF (20 ml) reflux for 2h, cooled then poured onto ice. The yielded solid filtered off and crystallized from dioxan to give 14 as deep-brown crystals, yield 80%, m.p. 198-200˚C. Analytical data found: C, 59.89; H, 3.01; F, 2.98; N, 16.59%. Calculated for C₂₉H₁₉FN₇PO₄ (579); C, 60.10; H, 3.28; F, 3.28, N, 16.92%. IR νcm⁻¹: 3139 (NH), 1694 (C=O), 1626, 1540 (C=N), 1305 (N-N), 1250 (C-F), 1157 (P=O), 1080 (Ph-O-P), 970, 900, 850, 811 (aryl CH).¹H NMR(DMSO) δ=10.76-10.61 (s, 1H, NH), 8.011 (s, 1H, NH-P=O), 7.67 - 7.28, 7.27 - 7.12, 7.05 - 6.94, 6.87 - 6.816 (each m, 17H, aryl and phenyl protons). ¹³CNMR (DMSO) δ: 163.77, 163.68, 162.45, 159.48, 157.32, 141.29, 136.82, 134.95, 95.133.65, 130.07, 122.27, 120.80, 120.30, 117.73, 117.57, 113.54, 113.50, 113.38, 112.10, 112.04, 110.79, 110.73, 108.09, 107.92, 105.34, 105.17, 77.67 - 77.24. M/Z (Int. %) 579 (581, M + 2; 13.15%) 331 (31.88), 275 (75.19), 248 (1.15); 141 (18.20), 95 (100), 93 (20.51), 63 (5.13).

3-Phenyl-1,2,3,4-tetrahydro-7-(5’-fluoro-2’-diphenyl phosphorylanilido)-1,2,4-triazino [4,3-b] [1,2,4] triazin- 8-one (15)

A mixture of 3 (0.01 mol) and phenacyl bromide (0.01 mol) in ethanolic KOH (5%, 20 ml) reflux for 2 h, then poured onto ice-HCl. The solid produced filtered off and crystallized from THF to give 15 as brownish crystals. Yield 65% m.p., 98˚C - 100˚C. Analytical data; Found: C, 59.98; H, 3.55; F, 3.20; N, 14.51%. Calculated for C_29­H₂₂FN₆PO₄ (568); C, 61.26; H, 3.87; F, 3.34; N, 14.78%. IR νcm⁻¹: 3158 (NH), 1655 (C=O), 1580 (C=N), 1474 (deform. CH₂), 1308 (N-N), 1230 (C-F), 1180 (P=O), 1092 (Ph-O-P), 980, 950, 900, 850, 801 (aryl CH).¹H NMR(DMSO) δ = 12.75 (s, 1H, NH), 10.78 (s, 1H, NH-P=O), 7.84 - 7.55, 7.49 - 7.30, 7.29 - 7.00, 6.99 - 6.79 (each m, 18H, aryl & phenyl protons). 3.4 (s, 2H, CH₂). ¹³C NMR (DMSO) δ:179.66, 163.04, 159.62, 158.02, 138.60, 129.51, 129.14, 128.67, 128.45, 128.18, 127.18, 126.89, 126.67, 125.86, 125.44, 123.31, 121.05, 120.20, 117.72, 117.56, 113.90, 113.74, 112.21, 112.13, 112.07, 110.47, 110.04, 108.10, 107.92, 77.72-77.29, 36.62.

7-(5’-Fluoro-2’-diphenylphophorylanilido)-1,2,3,4-tetrahydro-1,2,4-triazino[4,3-b][1,2,4]triazin-4,8-dione (16)

A mixture of 3 (0.01 mol) and monochloroacetic acid (0.01 mol) in DMF (20 ml) reflux for 2 h, cooled then poured onto ice. The solid thus obtained filtered off and crystallized from THF to give 16 as yellowish crystals. Yield 70%, m.p. 165˚C - 167˚C. Analytical data; found: C, 54.01; H, 3.25; F, 3.58; N, 16.31%. Calculated for C₂₃H₁₈FN₆PO₅ (508); C, 54.33; H, 3.54; F, 3.74; N, 16.53%. IR νcm⁻¹: 3382 (NH), 3224 (NH), 1685 (C=O), 1590 (C=N), 1477 (deform. CH₂), 1250 (C-F), 1180 (P=O), 1041 (Ph-O-P), 807, 760 (aryl CH). ¹H NMR (DMSO) δ: 12.97, 10.70, 10.42 (each s, 3H, 2NH, OH), 9.19 (s, 1H, NH-P=O), 7.99 - 7.00, 6.99 - 6.86, 6.85 - 6.79 (each m, 13H, aryl & phenyl protons), 4.33 (s, 2H, CH₂). ¹³C NMR (DMSO) δ = 173.41, 163.77, 163.67, 159.42, 157.84, 157.70, 136.69, 136.04, 121.23, 121.06, 113.87, 113.81, 113.24, 113.08, 111.48, 111.43, 110.966, 110.699, 111.644, 109.28, 107.00, 106.83, 105.02, 104.02, 78.08 - 77.65, 31.22.

7-(5’-Fluoro-2’-diphenylphosphorylanilido)-1,2-dihydro-1,2,4-triazino [4,3-b][1,2,4] triazin-3,8-dione (17)

Equimolar mixture of 3 and 1,1-dichloroacetic acid in DMF (20ml) reflux for 2h, cooled then poured onto ice. The yield obtained filtered and crystallized from dioxan to 17 as yellowish crystals. Yield 78%, m.p. 180˚C - 182˚C. Analytical data: found C, 54.03; H, 2.89; F, 3.55; N, 16.31%. Calculated for C₂₃H₁₆FN₆PO₅ (506); C, 54.54; H, 3.16; F, 3.75; N, 16.60%. IR νcm⁻¹: 3100 (NH), 1791 (C=O), 1655 (C=O), 1590 (C=N), 1547 (C=N), 1295 (N-N), 1235 (C-F), 1158 (P=O), 1094 (Ph-O-P), 984, 865, 830 (aryl CH).¹H NMR (DMSO) δ: 12.7 (s, 1H, NH), 10.53 (s, 1H, NH-P=O), 9.07 (s, 1H, CH=N), 7.91 - 7.16, 6.92 - 6.81, 6.77 - 6.71 (each m, 13H, aryl & aryl protons). ¹³C NMR(DMSO) δ:179.58, 163.82, 163.01, 162.39, 159.50, 157.92, 142.32, 138.56, 136.67, 136.03, 121.28, 121.12, 117.45, 115.59, 115.43, 113.90, 112.13, 111.47, 110.67, 109.50, 109.34, 108.08, 107.91, 107.12, 106.95, 77.88 - 77.45, 66.36.

7-(5’-Fluoro-2’-diphenylphosphorylanilido)-1,2,3,4-tetrahydro-1,2,4-triazino[4,3-b][4,34]triazin-3,4,8- trione (18)

A mixture of 3 (0.01 mol) in dry C₆H₆ treat with oxalyl chloride (0.01 mol) added dropwise then, TEA added drop wise (few drops) then heated under reflux for 2h, cooled. The solid produce filtered off and crystallized from C₆H₆ to give 18 as deep-yellowish crystals, yields 60%, m.p. 168˚C - 170˚C. Analytical data: found: C, 52.49; H, 2.85; F, 3.51; N, 15.88%. Calculated for C₂₃H₁₆FN₆PO₆ (522); C, 52.87; H, 3.06; F, 3.63; N, 16.09%. IR νcm⁻¹: 3382, 3319, 3156 (3NH), 1680 (C=O), 1557 (C=N), 1270 (C-F), 1143 (P=O), 1041 (Ph-O-P), 994, 860, 804 (aryl CH).¹H NMR (DMSO) δ: 14 (s, 1H, NH), 12.9 (s, 1H, NH), 10.8 (s, 1H, NH-P=O) 9.3, 8.50, 8.0 (each s, aryl protons), 7.45, 7.35, 7.039, 7.035, 7.031, 7.02, 6.886, 6.878, 6.870, 6.86 (m, 10H phenyl protons). ¹³C NMR (DMSO) δ: 167.31, 163.07, 159.53, 158.95, 129.48, 128.26, 120.21, 118.50, 118.26, 112.38, 112.33, 112.19, 112.14, 77.62 - 77.202. M/Z (Int.%) 522 (525, M + 3, 18.55), 248 (3.15), 96 (23.11), 95 (100), 93 (8.9), 68 (15.0).

The acid hydrazido derivative 20

A mixture of 3 (0.01 mol) and oxazolone19 (0.01 mol) in ethanol (50 ml) with H₂O (20 ml) reflux for 2 h, cooled then poured onto ice. The produced solid filtered off and crystallized from dioxan to give 20 as yellow crystals. Yield 58%, m.p. 155-157˚C. Analytical data; found: C, 59.89, H, 3.55, F, 5.00; N, 13.05%. Calculated for C₃₇H₂₈F₂N₇PO₆ (735); C, 60.40; H, 3.80; F, 5.17; N, 13.13%. IR νcm⁻¹: 3600 - 3200 (b, OH, NH, NH), 1592 (CONH), 1480 (deform. CH=C), 1240 (C-F), 1170 (P=O), 1050 (Ph-O-P), 850, 752 (aryl CH).

3-[5’-(4’’-Fluorophenylidene)-3’-phenyl-1’H-6’-oxo-1’,2’,4’-triazin-2’-yl]-6-(5’-fluoro-2’-diphenylphospho- rylanilido)-1,2,4-triazin-5-(2H)one (21)

Compound 20 (1 mg) and glacial acetic acid (10ml) reflux for 2h, cooled then poured onto ice. The solid thus obtained filtered off and crystallized from ethanol to give 21 as deep yellowish crystals. Yield 80%, m.p. 233˚C - 235˚C, Analytical data; found: C, 61.81; H, 3.49; F, 5.09; N, 13.55%. Calculated for C₃₇H₂₆F₂N₇PO₅ (717); C, 61.92; H, 3.62; F, 5.29; N, 13.66%. IR νcm⁻¹: 3192 (NH), 2880, 2810 (aliphatic CH), 1699 (C=O), 1632 (CONH), 1479 (deform. CH=), 1303 (N-N), 1240 (C-F), 1210 (P=O), 1056 (Ph-O-P), 900, 870, 810, 801 (aryl CH).

6-[5’-fluoro-2’-(diphenylphosphato)aminophenyl]-3,3,3-triphenyl-3-λ⁵-1,2,4,3-triazaphopholino[4,5-b] [1,2,4]triazine-7(8H) one (22)

A mixture of compound 2 (0.01 mol) and triphenyl phosphine (0.01 mol) in acetonitryl (20ml) warm for 30 min, cooled. The solid obtained filtered off and crystallized from dioxan to give 22 as deep yellow crystals, yield 70%, m.p. 283˚C - 285˚C. Analytical data; found: C, 64.01; H, 4.15; F, 2.39, N, 11.35%. Calculated for C₃₉H₃₁FN₆P₂O₄ (728); C, 64.28; H, 4.25; F, 2.60; N, 11.53%. IR νcm⁻¹: 3300 - 3100 (b, NH, NH), 1694 (C=O), 1620 (C=N), 1307(N-N), 1264 (C-F), 1179 (P=O), 1027 (Ph-O-P), 910, 880, 793, 745 (aryl CH).

α-Aminophosphonic acids continue to elicit study due to interest in their biological properties as herbicides [22] , plant growth regulators [23] and most notably those species heaving a direct P-N bond are investigated as transition state analogues of the tetrahedral transition-state involved in peptide hydropysis [24] . Ali et al. [25] [26] studied the reactivity of α-amino phosphonates as dipolar ion structure and have type of tautomeric formula due to the higher e-withdrawing of two phenoxy and P=O groups (Figure 2). Thus, α-aminophosphonate group had

a higher degree of stability towards any attack of reagents, which attribute to presence of differ factors of stability [27] . Phosphorus elements in these systems, was determine by using the spectrophotomeric. The method is based on the development of floated complex of molybdophosphonic acid (MPA) and methylene blue (MB) with N, N’-diphenylbenzamide (DPBA) in toluene and its subsequent dissolution in acetone [28] .

A series of some new fluorine substituted phosphoryl-amino-1,2,4-trinzines bearing a functionally pyrazole ring have been obtained via cycloaddition and/or cyclocodensation of 3-hydrazino-1,2,4-trinzinone3 with π-ac- ceptor activated carbon atom reagents. In addition, a type of 1,2,4-trinzino [4,3-b] [1,2,4] triazindiones have been also obtained from cyclocondensation of compound 3 with α, β-bifunctional oxygen and halogen compounds in different conditions. The former structures of the new products confirmed from correct elemental analysis and their spectral measurements. Keeping in view the diverse medicinal activities associated with organo-heterocyclilc systems substituted fluorine, phosphorus and 3-thioxo-1,2,4-trinzinone, which intend to construct novel fluorinated substituted phosphoryl amino bearing 1,2,4-triazinone moiety hoping to active additive effects towards their HIV-1 activity.

Human immunodeficiency virus type-1 is the causative agent of acquired immunodeficiency syndrome (AIDS) which is one of the most serious health problems [42] . Since reverse transcriptase (RT) is an essential enzyme for the replication [43] of HIV, it is the most favoured target for the antiviral chemotherapy against HIV infection [44] . 3’-Azido-2’,3’-dideoxythymidine (AZT) [45] and 2’,3’-dideoxyinosine (DDI) [46] , 2’,3’-dideoxycyty- dine (DDC) [47] and 2’,3’-didehydro-3-deoxythymidine (DT4) [48] are the well-known potent nucleoside reverse transcriptase inhibitors clinical use, but unfortunately they produce serious side effects such as bone marrow suppression. The search for a more effective and less toxic agent has brought into focus potent yet structurally different non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) [49] . Shakil et al., [50] reported that increase or decrease of electro-negativity and hydrophobicity of the bioactive drugs, cytotoxicity will also increase or decrease accordingly. So less electronegative and less hydrophobic substituents would be preferred to design the less cytotoxic drugs. The large number of research papers published every year indicate that the development of an effective drug for the inhibition of HIV-1 via enzymes inhibitors [51] [52] . HIV PIs for example, prevent the cleavage of the gag and gag-pol precursor polyproteins to the structural proteins and functional proteins, thus arresting maturation and thereby blocking infectivity of the nascent virions. e.g. Tipranavir showed loss cross-resistance to HIV strains that were resistant to the established (peptidomimetic) inhibitors of HIV protease. Also, tipranavir retained marked activity against HIV-1 isolates derived from patients with multidrug resistance to other PIs (Figure 13).

In search for new poly substituted 1,2,4-triazine bearing a phosphoryl group. The present work is synthesize novel fluorine substituted phosphorylanilido-1,2,4-triazin-ones and evaluate as potential inhibitors for HIV-1. The procedure used in the National Cancer Institute’s Test for agents active against HIV is designed to detect agents acting at any stage of the virus reproductive cycle [53] . The assay basically involves the killing of T₄ lymphocytes by HIV. Small amounts of HIV are added to cells and two cycles of virus reproduction are necessary to obtain the required cell killing. Agents that interact with virions, cells or virus gene-products to inter- fere with viral activities will protect cells from cytolysis. The tetrazolium salt XTT is added to all wells and cultures are incubated to allow formazan color development by viable cells used analyzed spectrophotometrically (Figure 14).

Anti-HIV-1 screening results of some of compounds (Table 1) shows that these systems found inactive, probably due to their inability to exist in butterfly like conformation as explained in a similar case [54] . Only the compounds 7, 12, 18 and 22 exhibited a higher protection% (concentration required in protect MT-4 cells against the cytopathogenicity of HIV by 50%). The order reactivity increases as 18 > 10 > 7 > 12 > 22. A higher effect^'s of compound 18 (Table 2) is may be due to a higher possibility to form a type of H-bonds with proteins of virus, which led to a moderate degree of inhibition of HIV-1 activity. Also, compound 18 had a differ type of phenolic bonds, which give a variety of differ effects towards HIV-1 activity. Moreover, compound 18 had a less possibility to form a type of intra-molecular H-bond, thus their hydroxyl group become a higher degree of free action

with a active center of proteins of HIV-1 virus.

In search for new anti-HIV-1, novel fluorine substituted isolated and fused heterobicyclic nitrogen systems bearing 6-(2’-phosphorylanilido)-1,2,4-triazin moiety have been obtained from a ring closure reactions of the corresponding 3-hydrazino-1,2,4-triazinone with π-acceptable reagents. Some compounds exhibited a mark’s inhibitors as anti-HIV-1 activity in hope to a possible control on the HIV-1 activity.