English

• According to an estimate published in 2014 on statistics of the Joint United Nations Programme on Acquired Immune Deficiency Syndrome (UNAIDS), 36.9 million people (including 2.6 million infant and juvenile) were living with human immuno-deficiency virus (HIV), and 1.2 million people died from AIDS as well as related diseases in the same year^[1].Hence, the rapid global pandemic of AIDS has prompted an intense research progress in studying the pathogenic mechanism that could effec-tively inhibit HIV. Up to now, the reverse transcriptase (RT) of the HIV type 1 (HIV-1) plays a significant role in the viral replication process, which makes it a crucial target for the anti-HIV-1 inhibitor research^{[2, 3]}.Although numerous RT inhibitors, including primarily the nucleoside RT inhibitors (NRTIs) and the non-nucleoside RT inhibitors (NNRTIs), have been developed, like other anti-HIV inhibitors, effectiveness of now approved NRTIs and NNRTIs have been restricted because of the aggravation of the drug resis-tance^[4~7].To circumvent this challenge, there is an urgent need to discover, research and develop novel, selective, green, efficient and safe anti-HIV inhibitors with attractive potency against drug-resistant as well as wild RT viral strains, low cytoto-xicity and improved physicochemical properties^[8~11].

  To the best of our knowledge, hydrazones are excellent candidates for the study and development of antiprotozoal agents^{[12, 13]}, multidentate ligands^[14], insecticidal agents^{[15, 16]} and gelatinase inhibitors^[17]. However, little attention has been paid to the anti-HIV-1 activities of the N-phenyl-sulfonyl-3-acetylindole carbonyl hydrazones. In this work, a validated skeletal scaffold by our previous effort was still utilized as chemical prototype to design and prepare novel, selective, green, efficient as well as safe anti-HIV-1inhibitors. In our previous report, we have found that some compounds demonstrated potential anti-HIV-1 activity^[18~23]. Inspired by these previous observations, the aim in our program is to discover and develop new compounds with potent biological activity^[24~30]. We report here the results of the syntheses and anti-HIV-1 activities of a series of N-phenylsulfonyl-3-acetylindole carbonyl hydrazone derivatives bearing various functional groups. Additionally, a brief investigation of structure activity relationship (SAR) was also determined.

  1.   Experimental Section

  1.1   General

  All solvents and reagents were of reagent grade or purified according to standard methods before use. All melting points were determined on a digital melting point apparatus (Beijing Tech instrument Co., Ltd., Beijing, China) and were uncorrected. Thin-layer chromatography (TLC) was performed on Silica Gel 60 GF₂₅₄ (Qingdao Haiyang Chemical Co., Shandong, China). ¹H NMR and ¹³C NMR spectra were recorded on a Bruker Avance DMX 500 MHz instrument (Bruker Daltonik, Bremen, Germany) in DMSO-d₆ using tetramethylsilane (TMS) as the internal standard. ESI-TRAP-MS was carried out on a Bruker ESI-TRAP Esquire 6000 plus a mass spectrometry instrument (Bruker Daltonics, San Diego, California, USA). HR-MS was carried out on an IonSpec 4.7 T FTMS instrument (Bruker Daltonics, San Diego, California, USA). The purities of the target compounds were determined by RP-HPLC recorded on a Shimadzu LC-15C liquid chromatograph [SPD-15C UV-Vis spectrophotometric detector (190~700 nm); Shimadzu, Kyoto, Japan] using a Hypersil ODS C₁₈ column (5 μm, 4.6×150 mm) as the stationary phase.

  1.2   Compound purity assessment

  The purities of N-phenylsulfonyl-3-acetylindole carbonyl hydrazone derivatives 3a~3z were recorded on a Shimadzu LC-15C liquid chromatograph [SPD-15C UV-Vis spectrophotometric detector (190~700 nm)] using a flow rate of 1.0mL/min (MeOH/H₂O=5/1) and a Hypersil ODS C₁₈ column (5 μm, 4.6×150 mm) as the stationary phase, and which of them were over 95%.

  1.3   General procedures for the syntheses of N-phenylsulfonyl-3-acetylindole carbonyl hydrazone derivatives 3k, 3l, 3v, 3w

  As shown in Scheme 1, N-phenylsulfonyl-3-acetylindoles (1a or 1b, 0.5 mmol) and the corresponding hydrazides (2a~2d, 0. 5 mmol) in molar ratio 1∶1 were dissolved in 5 mL anhydrous alcohol. Two drops of acetic acid was added to the solution at ambient temperature. After finishing dropping, the above mixture was refluxed for 2~6 h until the reaction monitored by TLC was completed. Then the mixture was let stand for 10 minutes or until a larger amount of solid accumulated in the bottom of the flask. The gained solid was collected after filtration, and then washed with a certain amount of cool anhydrous alcohol until it was pure, monitored by TLC (petroleum ether/ethyl acetate, 1/1). Subsequently, the pure compounds were dried in vacuum drying chamber to afford the desired compounds 3k, 3l, 3v, 3w in 62%~88% yields.

  Scheme 1

  

  Scheme 1.  N-苯磺酰基-3-乙酰基吲哚羰基酰腙类衍生物3k、3l、3v、3w的合成路线

  Scheme 1.  Synthetic route for the preparation of N-phenylsulfonyl-3-acetylindole carbonyl hydrazone derivatives 3k, 3l, 3v, 3w

  下载: 全尺寸图片 幻灯片

  N-(4-ethyl)phenylsulfonyl-3-acetyl-6-me-thy lindole cyanoacetyl hydrazone (3k): E/Z=2/1, White solid, yield 62%, m.p. 238~240℃. ¹H NMR (500 MHz, DMSO-d₆) δ: 10.97 (s, 0.66H), 10.76 (s, 0.34H), 8.42~8.44 (m, 0.34H), 8.22 (d, J=8.0 Hz, 1H), 8.09~8.10 (m, 0.66H), 7.99 (d, J=7.5 Hz, 2H), 7.78 (s, 1H), 7.46 (d, J=7.5 Hz, 2H), 7.17~7.19 (m, 1H), 4.26 (s, 1.37H), 3.92 (s, 0.73H), 2.63~2.65 (m, 2H), 2.46 (s, 3H), 2.33 (s, 3H), 1.13 (t, J=3.5 Hz, 3H). ¹³C NMR (126 MHz, DMSO-d₆) δ: 165.8, 159.9, 151.9, 147.0, 135.7, 135.6, 134.6, 129.6, 128.2, 128.0, 127.4, 126.2, 126.0, 125.2, 124.4, 123.7, 121.7, 121.5, 116.6, 116.4, 113.3, 113.2, 28.4, 25.7, 25.2, 21.9, 15.3, 15.1, 15.0. MS (ESI-TRAP), m/z (%): 423 ([M + H]⁺, 100). HR-MS (ESI): Calcd for C₂₂H₂₃N₄O₃S ([M + H]⁺), 423.1413; found, 423.1416.

  N-(4-ethyl)phenylsulfonyl-3-acetyl-6-me-thylindole benzoyl hydrazone (3l): White solid, yield 81%, m.p. 202~204℃. ¹H NMR (500 MHz, DMSO-d₆) δ: 10.79 (s, 1H), 8.58 (d, J=6.0Hz, 1H), 8.23 (s, 1H), 8.00 (d, J=8.0 Hz, 2H), 7.93 (d, J=5.5 Hz, 2H), 7.79 (s, 1H), 7.61 (t, J=6.5 Hz, 1H), 7.48~7.54 (m, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.19 (d, J=5.5 Hz, 1H), 2.65 (q, J=8.5 Hz, 2H), 2.47 (s, 3H), 2.45 (s, 3H), 1.14 (t, J=7.5 Hz, 3H). ¹³C NMR (126 MHz, DMSO-d₆) δ: 164.3, 151.9, 145.3, 135.7, 135.6, 134.7, 134.5, 132.0, 129.6, 128.8, 128.3, 127.9, 127.4, 126.0, 125.7, 124.7, 122.1, 113.2, 28.4, 21.9, 15.1. MS (ESI-TRAP), m/z (%): 482 ([M + Na]⁺, 100). HR-MS (ESI): Calcd for C₂₆H₂₆N₃O₃S ([M + H]⁺), 460.1617. found, 460.1621.

  N-(3-nitro)phenylsulfonyl-3-acetyl-6-me-thylindole 4-pyridylformyl hydrazone (3v): White solid, yield 88%, m.p. 218~220℃. ¹H NMR (500 MHz, DMSO-d₆) δ: 8.83 (s, 2H), 8.76~8.78 (m, 1H), 8.63 (d, J=7.5 Hz, 1H), 8.39~8.54 (m, 3H), 8.06 (d, J=8.5 Hz, 1H), 7.92~7.96 (m, 1H), 7.83 (s, 2H), 7.21 (d, J=8.0 Hz, 1H), 2.58 (s, 3H), 2.46 (s, 3H). ¹³C NMR (126 MHz, DMSO-d₆) δ: 194.3, 150.6, 148.8, 138.3, 136.4, 135.0, 134.1, 133.4, 132.6, 132.5, 130.1, 127.0, 125.3, 122.5, 122.3, 121.9, 113.3, 28.3, 21.8. MS (ESI-TRAP), m/z (%): 478 ([M + H]⁺, 100). HR-MS (ESI): Calcd for C₂₃H₂₀N₅O₅S ([M + H]⁺), 478.1107. found, 478.1111.

  N-(3-nitro)phenylsulfonyl-3-acetyl-6-me-thylindole 4-methoxylbenzoyl hydrazone (3w): Yellow solid, yield 86%, m.p. 216~218℃. ¹H NMR (500 MHz, DMSO-d₆) δ: 10.65 (s, 1H), 8.76 (s, 1H), 8.59 (s, 1H), 8.50~8.54 (m, 2H), 8.34 (s, 1H), 7.93 (t, J=8.0 Hz, 3H), 7.83 (s, 1H), 7.20 (s, 1H), 7.07 (d, J=8.5 Hz, 2H), 3.85 (s, 3H), 2.48 (s, 3H) 2.45 (s, 3H). ¹³C NMR (126 MHz, DMSO-d₆) δ: 162.3, 148.6, 138.6, 136.1, 135.7, 133.1, 132.4, 130.3, 129.8, 127.7, 126.4, 125.9, 124.9, 123.1, 122.1, 114.0, 113.2, 55.9, 21.9, 15.1. MS (ESI-TRAP), m/z (%): 507 ([M + H]⁺, 100). HR-MS (ESI): Calcd for C₂₅H₂₃N₄O₆S ([M+ H]⁺), 507.1260. found, 507.1265.

  1.4   Anti-HIV-1 activity assay

  1.4.1   Virus and cells

  The laboratory-derived virus (HIV-1_IIIB) and cell line (C8166) were obtained from the Medical Research Council (MRC), AIDS Reagent Project, in London, United Kingdom. C8166 was maintained in RPMI-1640 medium supplemented with 10% heat-inactivated newborn calf serum (Gibco, Grand Island, New York, USA). The cells used in all experiments were in log-phase growth. The 50% HIV-1_IIIB tissue culture infectious dose (TCID₅₀) in C8166 cells was determined and calculated by the Reed and Muench method.Virus stocks were stored in small aliquots at -70 ℃^[31].

  1.4.2   MTT-based cytotoxicity assay.

  Cellular toxicity of tested compounds 3a~3z on C8166 cells was assessed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) method as described previously. Simply, cells were seeded in a 96-well microtiter plate in the presence or absence of various concentrations of compounds in triplicate and incubated at 37 ℃ in a humid atmosphere of 5% CO₂ for 3d. The supernatants were discarded, and MTT reagent (5 mg/mL in PBS) was added to each well, and then incubated for 4 h, after which 100 μL of 50% dimethyl formamide (DMF)-20% SDS was added. After the formazan was dissolved completely, the plates were read on a BioTek Elx 800 ELISA reader (BioTek, Winooski, Vermont, USA) at 595/630 nm. The cytotoxic concentration that caused the reduction of viable C8166 cells by 50% (CC₅₀) was determined from the dose-response curve.

  1.4.3   Syncytia assay

  In the presence of 100μL of various concentrations of tested compounds 3a~3z, C8166 cells (4×10⁵/mL) were infected with HIV-1_IIIB at a multiplicity of infection (M.O.I) of 0.06. The final volume per well was 200 μL. Control assays were performed without the testing compounds in HIV-1_IIIB infected and uninfected cultures. After 3d of culture, the cyto pathic effect (CPE) was measured by counting the number of syncytia. Percentage inhibition of syncytia formation and the 50% effective concentration (EC₅₀) was calculated. 3′-Azido-3′-deoxythymidine (AZT; Sigma-Aldrich, St. Louis, Missouri, USA) was used as a positive control. The therapeutic index (TI) was calculated as CC₅₀/EC₅₀^[32].

  2.   Results and Discussion

  2.1   Preparations of N-phenylsulfonyl-3-acetylindole carbonyl hydrazone derivatives 3a~3z

  N-Phenylsulfonyl-3-acetylindole carbonyl hydra- zones (3a~3j, 3m~3u, 3x~3z) were synthesized and characterized according to the procedures previously published^[15], while the rest of hydra-zones (3k, 3l, 3v, 3w) were smoothly synthesized as shown in Scheme 1. N-Phenylsulfonyl-3-acetylin-doles (1a, 1b) reacted with the corresponding hydrazides (2a~2d) in the presence of AcOH at reflux, and compounds 3k, 3l, 3v, 3w were prepared, as well as characterized by satisfactory ¹H NMR, ¹³C NMR, MS, HR-MS and m.p. Further-more, to determine the precise three-dimensional structural information and configuration of 3a~3z, the single-crystal structure of 3o was confirmed by X-ray crystallography as shown in previously published paper^[15]. It demonstrated that the substituents on the C＝N bond of 3o adopted a trans configuration. If the substituents on the C＝N bond of 3o adopted a cis configuration, big steric effects could be observed between the indolyl ring and the arylcarbonylamino group. Owing to the steric hindrance, the substituents on the C＝N bond of all compounds (except E/Z=2/1 for 3k) adopted a trans configuration (E configuration)^{[12, 15, 33]}.

  Interestingly, all reactants dissolved fine in anhydrous ethanol at the first of the reaction. As the reaction proceeded normally, some insoluble substance was gradually precipitated out, as well as an abundant of solid accumulated in the bottom of the flask at the end of the reaction. As a result if this behavior, all the desired N-phenylsulfonyl-3-acetylindole carbonyl hydrazones (3a~3z) could be obtained by filtration. This procedure imbues the synthetic methodology with green credentials.

  2.2   Anti-HIV-1 activities of N-phenylsul-fonyl-3-acetylindole carbonyl hydrazone der-ivatives 3a~3z

  As our ongoing work on research of anti-HIV-1 inhibitors, an array of N-phenylsulfonyl-3-acetylin-dole carbonyl hydrazone derivatives 3a~3z were designed, synthesized as well as evaluated in vitro for their inhibitory activity against HIV-1 replication in sensitively infected C8166 cells, and the 3′-azido-3′-deoxythymidine (AZT) was used as a positive control presented in Tab. 1. The results of anti-HIV-1 activity assay revealed that among the 26 evaluated compounds, two compounds (3a and 3t) display the most potent activity (EC₅₀ values of 0.77 and 0.74μg/mL, TI values of >259.74 and >270.27, respectively), and four compounds (3g and 3w~3y) exhibit significant anti-HIV-1 activity (EC₅₀ values of 1.88, 1.60, 1.69 and 1.79 μg/mL, TI values of 100.09, >125.00, >118.34 and >111.73, respectively), and six compounds (3e, 3i, 3l, 3m, 3o and 3v) showed moderate activity (EC₅₀ values of 3.60, 2.98, 3.74, 2.38, 3.91 and 3.46 μg/mL, TI values of >55.56, >67.11, >53.48, >84.03, >51.15 and >57.80, respectively), while the rest of target compounds exhibit relatively weak HIV-1 inhibitory activity (TI < 50).

  Table 1

  

  表 1  N-苯磺酰基-3-乙酰基吲哚羰基酰腙类衍生物3a~3z的抗HIV-1活性

  Table 1.  Anti-HIV-1 activities of N-phenylsulfonyl-3-acetylindole carbonyl hydrazine derivatives 3a~3z in vitro^a

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  Compound	R1	R2	R3	CC50b/(μg/mL)	EC50c/(μg/mL)	TId
  3a	H	H	(3-Me)Ph	> 200	0.77	> 259.74
  3b	H	H	(4-OMe)Ph	16.13	9.91	1.63
  3c	H	H	(3-Cl)Ph	31.10	1.96	15.87
  3d	H	4-Me	(3-Me)Ph	> 200	9.32	> 21.66
  3e	H	3-NO2	(3-Me)Ph	> 200	3.60	> 55.56
  3f	H	3-NO2	(4-OMe)Ph	> 200	17.41	> 11.49
  3g	H	3-NO2	(3-Cl)Ph	188.16	1.88	100.09
  3h	H	3-NO2	(4-NO2)Ph	116.73	16.20	7.21
  3i	6-Me	H	(4-OMe)Ph	> 200	2.98	> 67.11
  3j	6-Me	H	(4-NO2)Ph	25.07	8.71	2.88
  3k	6-Me	4-Et	CH2CN	> 200	57.85	> 3.46
  3l	6-Me	4-Et	Ph	> 200	3.74	> 53.48
  3m	6-Me	4-Et	2-Thienyl	> 200	2.38	> 84.03
  3n	6-Me	4-Et	3-Pyridyl	> 200	11.26	> 17.76
  3o	6-Me	4-Et	(3-Me)Ph	> 200	3.91	> 51.15
  3p	6-Me	4-Et	(4-OMe)Ph	> 200	93.02	> 2.15
  3q	6-Me	4-Et	(3-Cl)Ph	22.93	9.56	2.40
  3r	6-Me	4-Et	(4-NO2)Ph	> 200	15.44	> 12.95
  3s	6-Me	4-Et	(4-OH)Ph	15.86	12.49	1.27
  3t	6-Me	3-NO2	2-Thienyl	> 200	0.74	> 270.27
  3u	6-Me	3-NO2	3-Pyridyl	15.58	1.85	8.42
  3v	6-Me	3-NO2	4-Pyridyl	> 200	3.46	> 57.80
  3w	6-Me	3-NO2	(4-OMe)Ph	> 200	1.60	> 125.00
  3x	6-Me	3-NO2	(3-Cl)Ph	> 200	1.69	> 118.34
  3y	6-Me	3-NO2	(4-NO2)Ph	> 200	1.79	> 111.73
  3z	6-Me	3-NO2	(4-OH)Ph	25.85	0.78	33.14
  AZTe	-	-	-	1139.47	0.00324	351688.3
  a Values are means of two separate experiments. b CC50 (50% cytotoxic concentration), concentration of drug that causes 50% reduction in total C8166 cell number. c EC50 (50% effective concentration), concentration of drug that reduces syncytia formation by 50%. d In vitro therapeutic index (CC50 value/EC50 value). eAZT was used as a positive control.

  In order to elucidate the HIV-1 inhibitory activities of 3a~3z at a molecular basis and expose the structural features critical for their activities, a brief structure activity relationship (SAR) was determined to reveal the relationship between the substituents on 3a~3z and the anti-HIV-1 activity. In general, electron enough of the indolyl ring and electron deficiency of the phenyl ring of the N-arylsulfonyl group could favor the anti-HIV-1 activity (e.g., 3t vs 3m and 3w~3z vs 3p~3s). To be specific, (1) When R¹ and R² are H, introduction of R³=(3-Me)Ph could result in the pronounced compound (3a vs 3b and 3c), EC₅₀ values of 0.77, 9.91 and 1.96 μg/mL, TI values of >259.74, 1.63 and 15.87, respectively; that is, the TI value of 3a is more than 16 times of that of 3c and close to 160 times of that of 3b. (2) When R¹=H and R²=3-NO₂, compounds with R³=(3-Cl)Ph exhibits significant HIV-1 inhibitory activity (3g vs 3e, 3f and 3h). For example, the EC₅₀ and TI values of 3g and 3h are 1.88, 16.20 μg/mL, and 100.09, 7.21, respectively. The TI value of 3g is close to 14 times of that of 3h. (3) R³=2-Thienyl plays a vital role in the activity against the HIV viral replication. For example, the EC₅₀ and TI values of compounds 3t and 3m are 0.74, 2.38 μg/mL, and >270.27, >84.03, respectively. (4) Interestingly, when R¹=6-Me, R²=3-NO₂ is more significant for the anti-HIV-1 activities than R²=4-Et (TI >270.27 for 3t vs TI >84.03 for 3m; TI >125.00 for 3w vs TI > 2.15 for 3p; TI >118.34 for 3x vs TI=2.40 for 3q; TI >111.73 for 3y vs TI >12.95 for 3r; TI=33.14 for 3z vs TI=1.27 for 3s); when R²=3-NO₂, R¹=6-Me is more significant for the anti-HIV-1 activities than R¹=H (TI >125.00 for 3w vs TI >11.49 for 3f; TI >118.34 for 3x vs TI=100.09 for 3g; TI >111.73 for 3y vs TI=7.21 for 3h). (5) R¹=6-Me and R²=3-NO₂ also play a pivotal role in the activity against the HIV viral replication, and the corresponding compounds 3t~3z (except TI=8.42 for 3u) frequently display more potent anti-HIV-1 activity. For example, the TI values of compounds 3t and 3v~3z are >270.27, >57.80, >125.00, >118.34, >111.73 and 33.14, respectively.

  At the same time, some interesting and valuable views are obtained by comparing the previous results of our research group^{[21, 22]}. Overall, as described in Figure 1, R¹=H, 6-Me, 5-NO₂ or 5-CN plays a pivotal role in the anti-HIV-1 activity; R²=H, 4-Me or 3-NO₂ is acceptable, and also plays an important role in the activity; R³=Ph, (3-Me)Ph, (4-OMe)Ph, (3-Cl)Ph, (4-NO₂)Ph or 2-thienyl is usually crucial; the proper chain length of R⁴ (H or Me) is essential for activity. Rational choice of substituents of R¹, R², R³ and R⁴ on hydrazone (Fig. 1) is an effective way to obtain potential anti-HIV-1 compounds in the future. Therefore, further chemical modifications should be deliberately manipulated so as to exploit more potent inhibitors. These results will pave the way for further preparation of hydrazone in the development of promising and pronounced anti-HIV-1 agents. Further research on the structure-anti-HIV-1 activity relationships of hydrazine derivatives are being pursued in our laboratory.

  Figure 1

  

  图 1.  腙衍生物的结构与抗HIV-1活性关系的简述

  Figure 1.  Brief description of structure-anti-HIV-1 activity relationships of hydrazone derivatives

  下载: 全尺寸图片 幻灯片

  3.   Conclusion

  In summary, an array of N-arylsulfonyl-3-acylindole benzoyl hydrazone derivatives (3a~3z) was designed according to the molecular hybridization and further prepared by means of a modified route. This procedure imbues the synthetic methodology with green credentials. Subsequently, all the reported analogues were well evaluated for their anti-HIV-1 activity in vitro. Among them, compounds 3a, 3g, 3t and 3w~3y display significant anti-HIV-1 activity with EC₅₀ values of 0.77, 1.88, 0.74, 1.60, 1.69 and 1.79 μg/mL, and TI values of >259.74, 100.09, >270.27, >125.00, >118.34 and >111.73, respectively. Especially N-phenylsulfonyl-3-acetylindole 3-methylbenzoyl hydrazone (3a) and N-(3-nitro)phenylsulfonyl-3-acetyl-6-methylindole 2-thienylformyl hydrazine (3t) exhibit the best anti-HIV-1 activity.

  
  
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  Scheme 1  Synthetic route for the preparation of N-phenylsulfonyl-3-acetylindole carbonyl hydrazone derivatives 3k, 3l, 3v, 3w

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  Figure 1  Brief description of structure-anti-HIV-1 activity relationships of hydrazone derivatives

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  Table 1.  Anti-HIV-1 activities of N-phenylsulfonyl-3-acetylindole carbonyl hydrazine derivatives 3a~3z in vitro^a

  Compound	R1	R2	R3	CC50b/(μg/mL)	EC50c/(μg/mL)	TId
  3a	H	H	(3-Me)Ph	> 200	0.77	> 259.74
  3b	H	H	(4-OMe)Ph	16.13	9.91	1.63
  3c	H	H	(3-Cl)Ph	31.10	1.96	15.87
  3d	H	4-Me	(3-Me)Ph	> 200	9.32	> 21.66
  3e	H	3-NO2	(3-Me)Ph	> 200	3.60	> 55.56
  3f	H	3-NO2	(4-OMe)Ph	> 200	17.41	> 11.49
  3g	H	3-NO2	(3-Cl)Ph	188.16	1.88	100.09
  3h	H	3-NO2	(4-NO2)Ph	116.73	16.20	7.21
  3i	6-Me	H	(4-OMe)Ph	> 200	2.98	> 67.11
  3j	6-Me	H	(4-NO2)Ph	25.07	8.71	2.88
  3k	6-Me	4-Et	CH2CN	> 200	57.85	> 3.46
  3l	6-Me	4-Et	Ph	> 200	3.74	> 53.48
  3m	6-Me	4-Et	2-Thienyl	> 200	2.38	> 84.03
  3n	6-Me	4-Et	3-Pyridyl	> 200	11.26	> 17.76
  3o	6-Me	4-Et	(3-Me)Ph	> 200	3.91	> 51.15
  3p	6-Me	4-Et	(4-OMe)Ph	> 200	93.02	> 2.15
  3q	6-Me	4-Et	(3-Cl)Ph	22.93	9.56	2.40
  3r	6-Me	4-Et	(4-NO2)Ph	> 200	15.44	> 12.95
  3s	6-Me	4-Et	(4-OH)Ph	15.86	12.49	1.27
  3t	6-Me	3-NO2	2-Thienyl	> 200	0.74	> 270.27
  3u	6-Me	3-NO2	3-Pyridyl	15.58	1.85	8.42
  3v	6-Me	3-NO2	4-Pyridyl	> 200	3.46	> 57.80
  3w	6-Me	3-NO2	(4-OMe)Ph	> 200	1.60	> 125.00
  3x	6-Me	3-NO2	(3-Cl)Ph	> 200	1.69	> 118.34
  3y	6-Me	3-NO2	(4-NO2)Ph	> 200	1.79	> 111.73
  3z	6-Me	3-NO2	(4-OH)Ph	25.85	0.78	33.14
  AZTe	-	-	-	1139.47	0.00324	351688.3
  a Values are means of two separate experiments. b CC50 (50% cytotoxic concentration), concentration of drug that causes 50% reduction in total C8166 cell number. c EC50 (50% effective concentration), concentration of drug that reduces syncytia formation by 50%. d In vitro therapeutic index (CC50 value/EC50 value). eAZT was used as a positive control.

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