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International Journal of HIV/AIDS and Research (IJHR)  /  IJHR-2379-1586-02-201

Synthesis and Anti Hiv-1 Reverse Transcriptase Evaluation of A Series of N-Mono Substituted Thiourea Derivatives

G. Meng1*, M. Wang1, M. S. Dong2, A. Q. Zheng3, J. Shi1, E. De Clercq4, C. Pannecouque4, J. Balzarini4

1 School of Pharmacy, Health Science Center, Xi’an Jiaotong University, Xi’an, P. R. China.
2 School of Software Engineering, Xi’an Jiaotong University, Xi’an, P. R.China.
3 School of Science, Xi’an Jiaotong University, Xi’an, P. R. China.
4 Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.

*Corresponding Author

Ge Meng,
School of Pharmacy,
Health Science Center, Xi’an Jiaotong University,
Xi’an, Shaanxi 710061, P. R. China.

Received: January 31, 2015; Accepted: March 12, 2015; Published: March 17, 2015.

Citation: G. Meng et al., (2015) Synthesis and Anti Hiv-1 Reverse Transcriptase Evaluation of a Series of N-Mono Substituted ThioureaDerivatives. Int J AIDS Res. 02(2), 19-27. doi:

Copyright: G. Meng© 2015. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.


Thirteen kinds of N-monosubstituted thioureas have been synthesized from various primary amines through three different methods. The chemical structures of all the compounds have been characterized by the various spectral analyses. Four of them were evaluated for the anti-HIV-1 activity. The results showed that compound 1b, showing the IC50 = 29.7 (μg/ mL) to the strain of ROD of HIV-1, CC50 > 50 (μg/mL), SI (selectivity index) > 2, was the best one among the test compounds. As for other compound 1a, 1c and 1d, the SI of them was less than 1, which means that these compounds might be toxic at the therapeutic level. Both the steric, electronic and topologic descriptors of the molecules were calculated to assist understanding the basic relationship between the structure and the biological activity. The docking result of 1c with HIV-1 reverse transcriptase (HIV-1 RT, PDB ID: 2HNZ) showed that there were still more unexploited rooms in the active site of the binding pocket of HIV-1 RT with compounds 1c

3.Materials and Methods
    3.1 Experimental Section
4.Result and Discussions
    4.1 Discussion About the Synthesis Method


Mono-Substituted Thioureas; Anti-HIV Activity; Molecular Descriptors; SAR; CADD; DOCK.


As the important classes of compounds [76], thioureas could be used as the versatile reagents [56] and building blocks for constructing the S,N-containing heterocyclic compounds as well as the substrates for the further structural modification. Beside being oxidized into ureas [74] or alkylated into isothioureas [77], they were widely used to construct thiazole [5, 28, 61, 75, 8,7, 91, 92] 2-thiouracil [50], aminothiazole [25 28, 51, 62, 69, 75, 93, 95] aminobenzothiazoles [34, 90] iminothiazolines [2>, 36, 54, 60] thiohydantoins [38, 39] 1, 3, 5-triazines [14], 2-aminooxazolidines [26], thiazolididiones [51, 53, 55], fused and spiro N/S-containing heterocycles [4]. The most interesting aspects of this type of compounds are the potent heterogeneous biological activities [58],such as anti-HIV activity [6], antituberculosis activity [35], cytokinin activity [8], promoting effect on wheat growth [94], reverses cross-links and restores biological activity in DNA, antimicrobial activity [13], anti-oxidant activity [1], anti-cancer activity [44, 73], tyrosinase inhibition [11, 84] and melanogenesis inhibition [83, 45]. The thiourea derivatives were also reported to be HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) for both the wild type [88], drug-resistant [49] and multidrug-resistant virus [86]. Among these active compounds, the anti-HIV agents have recently received much more attention than ever before, including the dual functional agents [12], PETTs [6, 64,67, 80] , ITUs [15, 48].

N-monosubstituted thioureas are biologically attractive for containing the primary NH2 group, serving as a hydrogen bond donor [30] to interact with the amino acid residues in the binding pocket of target enzymes [84] especially the reverse transcriptase (RT) during the HIV-1 life cycle. Therefore, as part of our research program for the possible anti-HIV-1 RT agents [19, 46, 50, 52, 54, 96] we would like to report the synthesis and the anti-HIV RT evaluation of a series of N-mono substituted thioureas. The target compounds were obtained from various substituted amines [4] mainly by the method shown in Scheme 1. This procedure usually required three steps from benzoyl chloride [2] and ammonium thiocyanate, via an intermediate of aroyl isothiocyanate [3] to afford primary amine [4] followed by the basic hydrolysis to give the target compounds (1a-1j) [66].

Scheme 1. Method A for synthesizing mono-N-substituted thioureas.

Although the above method was tedious in overall procedures, it might give the relatively high yield. Some other synthesis methods were also developed to obtain N-mono substituted thioureas efficiently. They might also involve using the toxic or special reagents, such as CS2 [59], carbonothioic dichloride (thiophosgene) [42], hydrazine hydrate, [40] LiAlHSH [41] and TMS-Cl [9] via the harsh conditions, such as the high temperature, the long time and the tedious work-ups [40].

In some special circumstances, when above procedures described in the method A could not give the desired result; other alternative methods were used to achieve the target molecules such as Method B and Method C, which were illustrated in the following (Scheme 2-3), respectively.

Scheme 2. Method B for synthesizing mono-N-substituted thioureas.

Scheme 3. Method C for synthesizing mono-N-substituted thioureas.

It should be pointed out that the synthesis procedures have also been improved based on these traditionally reported methods. The chemical structures of all of these compounds have been characterized by the spectrum analysis as well as their physical data (Table 1).

Table 1. The Information for preparing substituted thioureas (1) from amine (4).

The anti-HIV activities of N-monosubstituted thioureas were measured using the MTT method via comparing with four FDAapproved drugs (Nevirapine, Zidovudine, Dideoxycitidine and Dideoxyinosine). The cells were infected with HIV-1 wild-type virus (IIIB) strain cell line and HIV-2 strain (ROD). The results were reported as the half maximal (50%) inhibitory concentration (IC50). Moreover, the cytotoxicity (CC50) values of the compounds for each strain line were also determined. The selective index (SI=CC50/IC50) indicating the specificity of the antiviral effect, was given for both virus strains (Meng et al. 2003).

Due to the poor solubility of the molecules, only four compounds in the target molecules were tested for their anti-HIV activities. The result showed that compound 1b, showing the IC50=29.7μg/ mL to the strain of ROD of HIV-1, CC50 > 50μg/mL, SI (selectivity index) > 2, was the best one among all the test compounds. The SI of other compound 1a, 1c and 1d were all less than 1, meaning these compounds might be toxic at the therapeutic level (Table 2).

Table 2. Anti- HIV-1 RT activity evaluations of N-mono substituted thioureas.
C1-4: were the reference compounds (Nevirapine, Zidovudine, Dideoxycitidine and Dideoxyinosine) as the controlling group.

The steric, electronic and topologic descriptors of the compounds have been calculated using Chem3D Ultra (Cambridge software package) to find some relationships between the biological activities and the chemical structure features (Table 3).

Table 3. The calculated descriptors of N-monosubstituted thioureas.

Materials and Methods

Experimental Section

General Methods and Materials

All materials were obtained from the commercial suppliers and used as received. Melting points were taken on an X-4 digital melting point apparatus and were uncorrected. The elemental analyses were performed on a Carlo-Elba 1106 elemental analyzer. IR spectra were recorded on a Nicolet FI-IR 360 spectrophotometer. 1H NMR and 13C NMR spectra were determined on a Bruker AM-400 (400 MHz) spectrometer with TMS as an internal standard. Chemical shifts were reported in δ. Mass spectra were measured on a HP5988A instrument by direct inlet at 70ev. All materials were obtained from the commercial suppliers and used as received.

1. Synthesis

General procedures for synthesizing N-mono-substituted (1): The N-mono-substituted thioureas were synthesized according to the following three methods (A, B, C) based on the different substituents on the aromatic ring. The general synthetic procedures were described as follows in details. The related descriptors of the desired thioureas obtained via calculating with Cambridge software package were also listed thereafter.

Method A: Benzoyl chloride (7.20 g, 50.0 mmol) was added drop wise to a solution of NH4SCN (4.20 g, 51.0 mmol) in dry acetone (25.0 mL). The mixture was stirred under refluxing for 15 mins. Heating was removed and appropriate substituted anilines (50.0 mmol) were added drop wise over a period of 15 mins. The reaction mixture was kept under refluxing for further 30 mins, and then cooled to room temperature before pouring into icy water (375 mL). The resulting precipitates were collected by filtration, washed with water or a cold mixture of water and methanol (1: 1) [28]. The yellow solids (various substituted benzoyl thioureas), were added to a solution of sodium hydroxide (NaOH, 7.50 g, 65.0 mL water) and stirred at 80°C for 30 mins [61]. The mixture was adjusted to pH=7 with hydrochloric acid (HCl, 10.0 %). The appeared precipitates were filtered and washed with water, recrystallized with ethanol and then dried to give the pure products (1a- 1g, 1i-1j) [66].

Method B: To a flask was added substituted aromatic amine (150 mmoL) and aqueous hydrochloride (1.0 N, 16.0 mL) or HCl (conc. 36%, 15.2 g, 15.0 mmol), after slightly heated, the mixture was added ammonium thiocyanate (NH4SCN, 12.6 g, 165 mmol), and then the temperature of the mixture was raised to 90°C for 2 hrs, and then stop heating to stay for 16~18 hrs, until there was a first portion of the yellow solid appeared from the solution. The solid was filtered and then the filtration was concentrated to give a second part of the yellow solids. The two parts were combined and heated to 100°C for 8 hrs. After being triturated and washed with water (5.0 mL×3), the solid was obtained from filtration. Further recrystallization with a mixed solvent petroleum and ether (3:2), ethanol or THF (especial when 3,4-dichloroaniline was chosen as the material) [78] afforded the white crystal like products (1j) [25].

Method C: A solution of aromatic amine (0.017 mol) in ethanol (15.0 mL) was stirred at room temperature while concentrated hydrochloric acid (37.4%, 2.14 mL) was added dropwise. The formed suspension was heated to reflux until being dissolved, to which was added with a solution of potassium thiocynate (2.60 g, 25.5 mmol) in ethanol (5.00 mL). The reaction mixture was stirred at reflux for 18 h. The precipitate formed upon cooling was dried under vacuum and recrystallized from ethanol to yield the desired compounds (1H) [27].

N-Phenylthiourea (1a). Synthesis method: Method A, Recrystalization solvent: Anhydrous ethanol, Form: White crystals, Yield 70.0%. mp. 178-179°C, lit. 148-150°C [22], 1H NMR (DMSO-d6, 400 MHz): δ 2.49 (br, 2H, -NH2), 7.10 (d, 2H, ArH-2, 6), 7.31 (dd, 2H, ArH-3, 5), 7.45 (dd, 1H, ArH-4), 9.66 (br, 1H, NH); 13C NMR (DMSO-d6, 100 MHz): δ 123.01 (Ar-C-4), 124.38 (Ar-C-2, 6), 128.67 (Ar-C-3, 5), 139.06 (Ar-C-1), 180.99 (C=S).

N-(p-Toly) lthiourea (1b). Synthesis method: Method A, Recrystalization solvent: Anhydrous ethanol, Form: White crystals, Yield 60.0%. mp. 201-202°C, lit. 181-183°C [27], 1H NMR (DMSO- d6, 400 MHz): δ 2.25 (s, 3H, CH3), 2.49 (br, 1H, -NH), 7.11 (d, 2H, ArH-2,6), 7.23 (d, 2H, ArH-3, 5), 9.55 (br, 2H, NH2); 13C NMR (DMSO-d6, 100 MHz): δ 20.47 (4-CH3), 123.33 (Ar-C- 3,5), 129.16 (Ar-C-2,6), 133.70 (Ar-C-4), 136.40 (Ar-C-1), 180.94 (C=S).

N-(3-Chloro-2-methylphenyl) thiourea (1c). Synthesis method: Method A, Recrystalization solvent: Anhydrous ethanol, Form: White crystals, Yield 81.0%. mp. 190-192°C, lit. 153-154°C [66], 1H NMR (DMSO-d6, 400 MHz): δ 2.20 (s, 3H, CH3), 3.32 (s, 2H, -NH2), 7.19 (m, 1H, ArH-5), 7.34 (d, 1H, ArH-6), 7.54 (d, 1H, ArH-6), 9.37 (br, 1H, NH); 13C NMR (DMSO-d6, 100 MHz): δ 15.05 (2-CH3), 126.97 (Ar-C-6), 127.09 (Ar-C-4), 127.34 (Ar-C-5), 133.18 (Ar-C-3), 133.87 (Ar-C-1), 138.79 (Ar-C-2), 181.86 (C=S).

N-(4-fluorophenyl) thiourea (1d). Synthesis method: Method A, Recrystalization solvent: Anhydrous ethanol, Form: White crystals, Yield 57.9%. mp. 173-175°C, lit. 164°C [16]. 1H NMR (DMSO-d6, 400 MHz): δ 3.44 (s, 2H, -NH2), 7.19 (d, 2H, ArH-2, 6), 7.49 (d, 2H, ArH-3, 5), 9.45 (br, 1H, NH).

N-(4-Bromophenyl) thiourea (1e). Synthesis method: Method A, Recrystalization solvent: Anhydrous ethanol, Form: White crystals, Yield 55.0%. mp. 198-200°C, lit. 171°C [23]. 1H NMR (DMSO-d6, 400 MHz): δ 3.34 (s, 2H, -NH2), 7.39 (d, 2H, ArH-2, 6), 7.47 (d, 2H, ArH-3, 5), 9.75 (br, 1H, NH).

N-(3,4-Dichlorophenyl) thiourea (1f). Synthesis method: Method A. Recrystalization solvent: Anhydrous ethanol, Form: White needle like crystals, Yield 67.0%. mp. 220-222°C, lit. 216- 217°C [78]. lit. 205-206°C [31], 1H NMR (DMSO-d6, 400 MHz): δ 3.33 (s, 2H, -NH2), 7.19 (m, 1H, ArH-2), 7.34 (d, 1H, ArH-6), 7.54 (d, 1H, ArH-5), 9.86 (br, 1H, NH); MS (m/z): 220 (M+H+).

N-(p -Aminosulphonylphenyl) thiourea (1g, also call as 4-thioureido-benzenesulfonamide). Synthesis method: Method A, Recrystalization solvent: Anhydrous ethanol, Form: Yellow to white needle like crystals, Yield 40.0%. mp. 212-214°C, lit. 206°C [79]. 1H NMR (DMSO-d6, 400 MHz): 3.33 (s, 2H, -NH2), 7.64 (d, 2H, ArH-2, 6), 7.72 (d, 2H, ArH-3, 5), 9.96 (br, 1H, NH).

N-(2-Trifluoromethylphenyl) thiourea (1H). Synthesis method: Method C, Recrystalization solvent: Anhydrous ethanol, Form: Yellow to white crystals, Yield 99.3 %. mp. 163-164°C, lit. 170°C, [71, 82, 87]. 1H NMR (DMSO-d6, 400 MHz): 6.56 (s, 2H, -NH2), 7.01 (d, 1H, ArH-6), 7.10 (dd, 1H, ArH-4), 7.26 (dd, 1H, ArH-5), 7.53 (d, 1H, ArH-3), 8.91 (br, 1H, NH).

N-(p-Methoxyphenyl) thiourea (1i). Synthesis method: Method A, Recrystalization solvent: Anhydrous ethanol, Form: White needle like crystals, Yield 85.7%. mp. 236-238°C, lit. 206-209°C [25], 212-214°C [65], 198-200°C [20], 210°C [85], 1H NMR (DMSO- d6, 400 MHz): 3.72 (s, 3H, OCH3), 6.87 (d, 2H, ArH-2, 6), 7.13 (d, 2H, H-3, H-5), 7.29 (br, 2 H, NH2), 9.02 (br, 1 H, NH).

N-(3-Trifluoromethylphenyl)thiourea (1j). Synthesis method: Method A, Recrystalization solvent: Anhydrous ethanol, Form: White crystals, Yield 70.5%. mp. 104-105°C, Synthesis method: Method B, Yield 49.2%, mp. 104-105°C, lit. 104-106°C (Kurzer and Canelle 1963), 103°C [21]. 1H NMR (DMSO-d6, 400 MHz): 6.09 (s, 2H, -NH2), 6.45 (d, 1H, ArH-6), 7.01 (s, 1H, ArH-2), 7.09 (d, 1H, ArH-4), 7.16 (dd, 1H, ArH-5), 8.68 (br, 1H, NH).

N-(3-Chloro-4-fluorophenyl)thiourea (1k). Synthesis method: Method A, Recrystalization solvent: Anhydrous ethanol, Form: White crystals, Yield 58.0%. mp. 193-195°C, lit. Triclinic crystals [70]. 1H NMR (DMSO-d6, 400 MHz): 5.96 (s, 2H, -NH2), 6.30 (d, 1H, ArH-6), 6.65 (s, 1H, ArH-2), 7.26 (d, 1H, ArH-5), 8.59 (br, 1H, NH).

N-(3,5-Ditrifluoromethylphenyl) thiourea (1l). Synthesis method: Method A, Recrystalization solvent: Anhydrous ethanol, Form: White crystals, Yield 31.9%. mp. 150-156°. The compound 1l has been prepared by a streamlined method [7]. 1H NMR (DMSO- d6, 400 MHz): 6.06 (s, 2H, -NH2), 6.96 (s, 2H, ArH-2, 6), 7.37 (s, 1H, ArH-4), 8.91 (br, 1H, NH).

N-(N’,N’-Diethylaminoethylene) thiourea (1m). Synthesis method: Method A, Recrystalization solvent: Anhydrous ethanol, Form: White needle crystals, Yield 62.4%. mp.122-124°C [24]. 1H NMR (DMSO-d6, 400 MHz): 1.10 (t, 6H, CH3 × 2), 2.79 (m, 4H, CH2×2), 2.56 (t, 4H, CH2 × 2), 2.95 (t, 4H, CH2 × 2), 8.69 (br, 1H, NH). Compounds 1m has been prepared from thiourea and diethylaminoethyl chloride via dissolving sodium in alcohol [24].

2. Biological Activity:

The general procedure for anti-HIV activity assay was described as the following. The anti-HIV activity and cytotoxicity of the compounds were evaluated against the wildtype HIV-1 strain IIIB and HIV-2 strain ROD in MT-4 cell cultures using the 3-(4, 5-dimethylthiazol- 2-yl)-2, 5-diphenyltetrazo lium bromide (MTT) method. Briefly, virus stocks were titrated in MT-4 cells and expressed as the 50% cell culture infective dose (CCID50). MT-4 cells were suspended in a culture medium at 1×105 cells/mL and infected with HIV at a multiplicity of infection of 0.02. Immediately after the viral infection, 100 μL of the cell suspension was placed in each well of a flat-bottomed micro titer tray containing various concentrations of the test compounds. The tested compounds were dissolved in DMSO at 50 mM. After 4 days of incubation at 37°C, the number of viable cells was determined using the MTT method. Compounds were tested in parallel for the cytotoxic effects in the uninfected MT-4 cells.

3. Molecular modeling

3.1 Calculation of the molecular descriptors: The various molecule descriptors, including both the steric and the electric descriptors were calculated by the options available modules in Cambridge software package. The explanations and category of the calculated descriptors were listed as the following. General descriptors included molecular weight (MW). Hydrophobic descriptors include the Log value of the partition coefficient (LogP), partition coefficient (PC). Steric descriptors included the following molecular refractory (MR), molecular shape index (Ovality), the number of hydrogen bond donor (HBD), the number of hydrogen bond acceptor (HBA). The descriptors calculated from CHEMPROPSTD included Connolly accessible area (CAA), Connolly molecular area (CMA) and Connolly solvent excluded volume (CSEV). Molecular topology index included a Balaban index (BI), number of rotatable bonds (NRB), polar surface area (PSA), radius (R), shape coefficient (SC) and total valence connectivity (TVC). Energy related index included the energy of the highest occupied molecular orbit (HOMO), the energy of the lowest unoccupied molecular orbit (LUMO) and the total energy after energy minimization by MM semi-empirical method (TE). To obtain these descriptors, molecular dynamics calculation and energy minimization were sequentially run on each of the molecule with default values (Step interval = 2.0 fs, Frame interval = 10 fs, Terminate after 10000 steps) at first, the molecular descriptors of 1a-1m were then computed via Chem3D Ultra (Cambridge software), respectively.

3.2 Docking analysis: The dock studies were performed using the molecular modeling package SYBYLX.2.0 (Company 2011). Tripos force field and Gasteiger-Hückel partial atomic charges were used for minimizing the molecules [18]. The minimum energy difference of 0.001 kcal/mol was set as a convergence criterion. While considering Surflex-Dock was an well-known software to understand the interaction between the small molecules with the target protein [17, 32, 33, 63, 81], using an idealized active site called a protomol, which was built from the hydrogen-containing protein mol2 file [72, 89]. The construction was based on the amino acid residues that constitute the active site tuned to produce a small and buried docking target [37]. Dock analysis of compound 1c with HIV-1 RT 2HNZ were carried out according to the normal procedures in Surflex-Dock workflow on a SYBYL-2.0 workstation using all the default values [47].

Result and Discussions

Discussion About the Synthesis Method

Method A was a conventional synthesis method to obtain Nmonosubstituted thioureas from primary amines, involved using benzoyl chloride as the assisting material. While heating primary amine directly with ammonium thiocyanate in acidic water instead of using any irritating agent, the whole process of the Method B involves less reaction time and easier work-up than the traditional methods (Scheme 2) [25]. As for the Method C [27], while considering KSCN was often used as the starting product for the synthesis of CS2, and therefore it can be used as a non-toxic agent to replace CS2 for preparing N-mono-substituted thioureas, especially in a one-pot and supported reagent methods (Scheme 3) [3]. As a summary, both method B and method C were convenient for involving less reaction steps, but some time their yield were not as good as that of method A.

As for the biological activity evaluation result for N-monosubstituted thioureas were listed in Tables 2 together with the reference compounds. Some compounds were not evaluated for anti-HIV-1 activity due to their poor solubility. Four of the 13 compounds were screened with two infected virus strains. The result showed that only one compound 1c, containing a methyl group at the othor-position of the phenyl group and a chloro atom at the meta- position of the phenyl group, showed the relative inhibitory activity against HIV-2 strain ROD (IC50=29.70μg/mL, SI > 2), other compounds exhibit almost no activity against both wildtype HIV-1 strain IIIB and HIV-2 strain ROD.

The most active molecule (1c) of the series was subjected to MM minimization, and then the HOMO and LUMO of compound 1c were calculated and shown in Figure 2. The properties of all the target molecules were calculated according the different kind of molecular descriptors listed as the following: steric descriptors including molecular weight (MW) and Connolly molecular area (CMA), etc. (Table 3).

Figure 1. The HOMO (Left) and LUMO (Right) of the compound 1c.

Figure 2. Docking of 1c with HIV-1 RT (PDB ID: 2HNZ).

As a summary, it was quite surprising that the compounds 1c show activity again HIV-2, although the rest tested compounds could not inhibit both the wild type and the HIV-2 strain line virus.

The molecule weight of 1c and other target molecule were much more less than that of the ligand of 2HNZ, in which the ligand is a PETT derivative with the name of 1-(2-(4-ethoxy-3-fluoropyridin- 2-yl)ethyl)-3-(5-methylpyridin-2-yl) thiourea (Ren et al. 2006). This might lead to the active binding pocket of HIV-1 RT was less sterically fulfilled when interacting with 1c (Both the left and right diagram, Figure 2). The phenyl ring of 1c was almost perpendicular to the aromatic phenyl ring of Tyr181 in the HIV-1 RT BP, which was not favorable for enhancing aromatic π-π stacking effect for steric reasons. (The right diagram, Figure 2).


To summarize, it should be cautious when trying to change the structure feature of PETT from di-substituted thiourea into the mono-substituted thiourea structures for achieving the possible potential anti-HIV-1 RT reagents. The simplification in the structural skeleton might decrease the biological activity for their poor solubility and less compatibility in the active binding pocket of HIV-1 RT.


The authors are grateful to the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, P. R. China (2011), the Shaanxi Province Science and Technology Research and Development Program of China, International Cooperation (2013KW31-04).


  1. Abdinbekova RT, AM Magerramov, MM Kurbanova, IA Rzaeva, V M Farzaliev, et al. (2005) Synthesis and antioxidant activity of N-substituted thiocarbamides. Kimya Problemlari Jurnali 3: 52-56.
  2. Amin KM, DEA Rahman,YA Al-Eryani (2008) Synthesis and preliminary evaluation of some substituted coumarins as anticonvulsant agents. Bioorg. Med. Chem 16(10): 5377-5388.
  3. Aoyama T, S Murata, Y Nagata, T Takido, M. Kodomari (2005) One-pot synthesis of N-allylthioureas using supported reagents. Tetrahedron Lett 46(29): 4875-4878.
  4. Attanasi OA, L De Crescentini, G Favi, P Filippone, G. Giorgi,et al. (2008) Simple construction of fused and spiro nitrogen/sulfur containing heterocycles by addition of thioamides or thioureas on cycloalkenyl-diazenes: examples of click chemistry. Tetrahedron Lett 64(17): 3837-3858.
  5. Attanasi O A, P Filippone, E Foresti, B Guidi, S Santeusanio (1999) Study of reactions between 1, 2-diaza-1,3-butadienes and N, N'-diaryl- or N, N'- dialkylthioureas. Tetrahedron Lett 55(47): 13423-13444.
  6. Bell FW, AS Cantrell, M Hoegberg, SR Jaskunas, NG Johansson, et al. (1995) Phenethylthiazolethiourea (PETT) compounds, a new class of HIV- 1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs. J. Med Chem 38(25): 4929-4936.
  7. Browne DL, MO Brien, P Koos, PB Cranwell, A Polyzos,et al. (2012) Continuous-flow processing of gaseous ammonia using a Teflon AF-2400 tube-in-tube reactor: Synthesis of thioureas and in-line titrations. Synlett 23(9): 1402-1406.
  8. Bruce M, J Zwar (1966) Cytokinin activity of some substituted ureas and thioureas. Proc. R. Soc. Lond., B, Biol. Sci 165 (999): 245-265.
  9. Ciszewski L, D Xu, O Repič, T J Blacklock (2004) Reductive alkylation of thioureas: a highly practical synthesis of unsymmetrical N, N'-disubstituted thioureas. Tetrahedron Lett 45(43): 8091-8093.
  10. Sybyl-X Molecular Modeling Software Packages, Version 2.0. TRIPOS Associates, Inc; St. Louis, MO, USA: 2011.
  11. Criton M, V Le Mellay-Hamon (2008) Analogues of N- hydroxy-N'-phenylthiourea and N-hydroxy-N'- phenylurea as inhibitors of tyrosinase and melanin formation. Bioorg. Med. Chem. Lett 18(12): 3607-3610.
  12. Cruz OJD, TK Venkatachalam, aFM Uckun (2000) Novel thiourea compounds as dual-function microbicides. Biol. Reprod 63(205): 196-205.
  13. Cunha S, FC Macedo Jr, GA Costa, MT Rodrigues Jr, RB Verde,et al. (2007) Antimicrobial activity and structural study of disubstituted thiourea derivatives. Monatshefte fur Chemie 138(5): 511-516.
  14. Dandia A, K Arya, M Sati (2004) Microwave assisted synthesis of fluorinated hexahydro 1, 3, 5-triazine derivatives in aqueous medium and one pot synthesis of 1, 2, 4-triazolo (4, 3-a) 1, 3, 5-triazines. Synth. Commun 34(6): 1141-1155.
  15. Das K, PJ Lewi, SH Hughes, E Arnold (2005) Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors. Prog. Biophys. Mol. Biol 88(2): 209-231.
  16. Dyson GM, RF Hunter, JWT Jones, ER Styles (1931) Unsaturation and tautomeric mobility of heterocyclic compounds of the thiazole type in relation to modern electronic conceptions. J. Indian Chem. Soc 8: 147-180.
  17. Ganapaty S, P Ramalingam, C Baburao (2008) Antimicrobial and antimycobacterial activity of some quinoxalines'N' bridgehead heterocycles. Asian. J Chem 20(5): 3353-3356.
  18. Gasteiger J, M Marsili (1980) Iterative partial equalization of orbital electronegativity— a rapid access to atomic charges. Tetrahedron 36(22): 3219- 3228.
  19. Ge M, L Zhen-Yu (2007) Interaction model between a new HIV-1 RT inhibitor with its NNBP, Kunming, Yunnan, In Oral Report on 5th Chemical Biology Conference.
  20. Goodyer CL, EC Chinje, M Jaffar, IJ Stratford, MD Threadgill (2003) Synthesis of N-benzyl- and N-phenyl-2-amino-4,5-dihydrothiazoles and thioureas and evaluation as modulators of the isoforms of nitric oxide synthase. Bioorg. Med. Chem 11(19): 4189-4206.
  21. Gupta KA, AK Saxena, PC Jain, PR Dua, CR Prasad, et al. (1983) Synthesis and biological activity of 2,6-disubstituted 3-aryl-4(3H)-pyrimidinones as potential CNS agents. Indian J. of Chem Sec 22(8): 789-794.
  22. Gupta M, A Sachan, S Pandeya, V Gangwar (2006) Synthesis and antimicrobial evaluation of substituted arylthioureas. Asian. J Chem 18(4): 2959- 2962.
  23. Gupta MK, SN Pandeya, GM Zaiad, V Gangwar (2010) Synthesis and anticonvulsant activity of halo-substituted aryl urea and thioureas. J Indain Chem Soc 87(11): 1421-1424.
  24. Hahl H, L Schutz (1929) Diethylaminoethyl thiourea and similar compounds (substitutes for ergot.). US.
  25. Hay MP, S Turcotte, JU Flanagan, M Bonnet, DA Chan, et al (2010) 4-Pyridylanilinothiazoles that selectively target von Hippel-Lindau deficient renal cell carcinoma cells by inducing autophagic cell death. J. Med. Chem 53(2): 787-797.
  26. Heinelt U, D Schultheis, S Jäger, M Lindenmaier, A Pollex,et al. (2004) A convenient method for the synthesis of 2-amino substituted aza-heterocycles from N, N′-disubstituted thioureas using TsCl/NaOH. Tetrahedron 60(44): 9883-9888.
  27. Heng S, KR Gryncel, ER Kantrowitz (2009) A library of novel allosteric inhibitors against fructose 1, 6-bisphosphatase. Bioorg. Med. Chem 17(11): 3916-3922.
  28. Holla BS, K Malini, BS Rao, B Sarojini, NS Kumari (2003) Synthesis of some new 2, 4-disubstituted thiazoles as possible antibacterial and anti-inflammatory agents. Eur J Med Chem 38(3): 313-318.
  29. Holla BS, KV Malini, BS Rao, BK. Sarojini, NS Kumari (2003) Synthesis of some new 2,4-disubstituted thiazoles as possible antibacterial and antiinflammatory agents. Eur J Med Chem 38(3): 313-318.
  30. Hritzová O, P Kutschy, J Imrich,T Schöffmann (1987) Hydrogen bonds in N-(3-chloro-2-benzo[b] thienocarbonyl) -and N-(2-benzo[b] thienocarbonyl)-N'-monosubstituted thioureas. Collect. Czech. Chem. Commun 52(11): 2673-2679.
  31. Hughes JL, R Liu, T Enkoji, CM Smith, JW Bastian, PD Luna (1975) Cardiovascular activity of aromatic guanidine compounds. J. Med Chem18(11): 1077-1088.
  32. Jain AN (2003) Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine. J. Med Chem 46(4): 499-511.
  33. Jain AN (2009) Effects of protein conformation in docking: improved pose prediction through protein pocket adaptation. J Comput Aided Mol Des 23(6): 355-374.
  34. Jordan AD, C Luo, AB Reitz (2003) Efficient conversion of substituted aryl thioureas to 2-aminobenzothiazoles using benzyltrimethylammonium tribromide. J. Org. Chem 68(22): 8693-8696.
  35. Karakuş S, S Rollas (2002) Synthesis and antituberculosis activity of new Nphenyl- N-[4-(5-alkyl/arylamino-1, 3, 4-thiadiazole-2-yl) phenyl] thioureas. Il Farmaco 57(7): 577-581.
  36. Kasmi S, J Hamelin,H Benhaoua (1998) Microwave-assisted solvent-free synthesis of iminothiazolines.Tetrahedron Letters 39(44): 8093-8096.
  37. Kellenberger E, J Rodrigo, P Muller, D Rognan (2004) Comparative evaluation of eight docking tools for docking and virtual screening accuracy. Proteins 57(2): 225-242.
  38. Kidwai M, A Jahan, D Bhatnagar (2010) Polyethylene glycol as an efficient and reusable solvent medium for the synthesis of thiohydantoins using K2CO3 as catalyst. J Sulphur Chem 31(3): 161-167.
  39. Kidwai M, R Venkataramanan, B Dave (2001) Solventless synthesis of thiohydantoins over K2CO3. Green Chem 3(6): 278-279.
  40. Kodomari M, M Suzuki, K Tanigawa, T Aoyama (2005) A convenient and efficient method for the synthesis of mono-and N, N-disubstituted thioureas.Tetrahedron Lett 46(35): 5841-5843.
  41. Koketsu M, Y Fukuta, H Ishihara (2001) Preparation of N, N-unsubstituted selenoureas and thioureas from cyanamides. Tetrahedron Lett 42(36): 6333-6335.
  42. Kovalenko SS, OV Zaremba, TA Borisova,VM Nikitchenko, SM Kovalenko, et al. (2008) Synthesis of combinatorial libraries of 3-substituted 2-methyl- 4-thioxo-3,4,5,6-tetrahydro-2H-2,6-methano-1,3,5-benzoxadiazocines and their 4-oxo analogs in the Biginelli reaction. Zh. Org. Farm. Khim 6: 38-45.
  43. Kurzer F, J Canelle (1963) Cyclization of 4-substituted 1-amidinothiosemicarbazides to 1, 2, 4-triazole and 1, 3, 4-thiadiazole derivatives. Tetrahedron 19(11): 1603-1610.
  44. Larsson B (1991) Melanin-affinic thioureas as selective melanoma seekers. Melanoma Res 1(2): 85-90.
  45. Lee KC, P Thanigaimalai, VK Sharma, MS Kim, E Roh, et al. (2010) Structural characteristics of thiosemicarbazones as inhibitors of melanogenesis. Bioorg. Med. Chem. Lett 20(22): 6794-6796.
  46. LiuY, G Meng, A Zheng, F Chen,W Chen, et al. (2014) Design and synthesis of a new series of cyclopropylamino-linking diaryl pyrimidines as HIV non-nucleoside reverse transcriptase inhibitors. Eur J Pharm Sci 62(62C): 334-341.
  47. BioPharmics LLC (2009) Surflex Manual: Docking and Similarity (version 1.3).
  48. Ludovici DW, MJ Kukla, PG Grous, S Krishnan, K Andries, et al. (2001) Evolution of anti-HIV drug candidates. part 1: From α-Anilinophenylacetamide (α-APA) to imidoyl thiourea (ITU). Bioorg Med Chem Lett 11(17): 2225-2228.
  49. Mao C, EA Sudbeck, T Venkatachalam, FM Uckun (2000) Structure-based drug design of non-nucleoside inhibitors for wild-type and drug-resistant HIV reverse transcriptase. Biochem. Pharmacol 60(9): 1251-1265.
  50. Meng G,F Chen, E De Clercq, J. Balzarini, C Pannecouque (2003) Nonnucleoside HIV-1 reverse transcriptase inhibitors: part I. synthesis and structure- activity relationship of 1-alkoxymethyl-5-alkyl-6-naphthyl methyl uracils as HEPT analogues. Chem. Pharm. Bull 51(7): 779-789.
  51. Meng G,Y Gao, ML Zheng (2011) Improved preparation of 2,4-thiazolidinedione. Org. Prep. Proc. Int 43(3): 312-313.
  52. Meng G, Y Kuang, L Ji, Fe Chen (2005) Synthesis of 1-[(2-hydroxyethoxy) methyl]-6-(5,6,7,8-tetrahydronaphthylmethyl-1)thymine as novel inhibitor against drug-resistant HIV mutants. Synth Commun 35(8): 1095-1102.
  53. Meng G, ZY Li, ML Zheng (2008) An efficient one-step method for synthesis of 2,4-thiazolidinedione. Org. Prep. Proc. Int 40(6): 572-574.
  54. Meng G, YLiu, A Zheng, FChen, W Chen, et al. (2014a) Design and synthesis of a new series of modified CH-diarylpyrimidines as the drug resistant HIV non-nucleoside reverse transcriptase inhibitors.Eur J Med Chem 82: 600-611.
  55. Meng G, ML Zheng, MS Dong, QH Qu (2012) An eco-friendly preparation of 2-iminothiazolidin-4-ones derivatives. Org. Prep. Proc. Int 44(2): 184-186.
  56. Meng G, ML Zheng, AQ Zheng, M Wang, J Shi (2014b) The novel usage of thiourea nitrate in aryl nitration. Chinese ChemLett 25(1): 87-89.
  57. Meng G, M Zheng, M Dong, M Wang, A Zheng, et al. (2014) An environmental- friendly synthesis of 2,3-disubstituted-2-iminothiazoline-4-ones. J. Heterocyclic Chem 51(S1): E1–E388
  58. Mitchell S, G Steventon (1994) Thiourea and its biological interactions. Sulfur Reports 16(1): 117-137.
  59. Muccioli GG, D Martin, GK Scriba, W Poppitz, JH Poupaert, et al. (2005) Substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one as CB1 cannabinoid receptor ligands: Synthesis and pharmacological evaluation. J. Med Chem 48(7): 2509-2517.
  60. Murru S, C Singh, V Kavala, BK Patel (2008) A convenient one-pot synthesis of thiazol-2-imines: application in the construction of pifithrin analogues. Tetrahedron 64(8): 1931-1942.
  61. Narayana B, RKK Vijaya, BV Ashalatha, NS Kumari, BK Sarojini (2004) Synthesis of some new 5-(2-substituted-1,3-thiazol-5-yl)-2-hydroxybenzamides and their 2-alkoxy derivatives as possible antifungal agents. Eur J Med Chem 39(10): 867-872.
  62. Narender M, MS Reddy, VP Kumar, B Srinivas, R Sridhar (2007) Aqueousphase one-pot synthesis of 2-aminothiazole-or 2-aminoselenazole-5-carboxylates from β-keto esters, thiourea or selenourea, and N-bromo-succinimide under supramolecular catalysis. Synthesis 0(22): 3469-3472.
  63. Pham TA, AN Jain (2008) Customizing scoring functions for docking. J Comput Aided Mol Des 22(5): 269-286.
  64. Ranise A, A Spallarossa, S Cesarini, F Bondavalli, S Schenone (2005) Structure- based design, parallel synthesis, structure-activity relationship, and molecular modeling studies of thiocarbamates, new potent non-nucleoside HIV-1 reverse transcriptase inhibitor isosteres of phenethylthiazolylthiourea derivatives. J. Med Chem 48(11): 3858-3873.
  65. Rasmussen C, F Villani Jr, L Weaner, B Reynolds, A Hood,et al. (1988a) Improved procedures for the preparation of cycloalkyl-, arylalkyl-, and arylthioureas. Synthesis (06): 456-459.
  66. Rasmussen C, F Villani Jr, L Weaner, B Reynolds, A Hood (1988b) Improved procedures for the preparation of cycloalkyl-, arylalkyl-, and arylthioureas. Synthesis (6): 456-459.
  67. Ren J, J Diprose, J Warren, RM Esnouf, LE Bird, et al. (2000) Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. J. Biol. Chem 275(8): 5633-5639.
  68. Ren J, CE Nichols, A Stamp, PP Chamberlain, R Ferris,et al. (2006) Structural insights into mechanisms of non-nucleoside drug resistance for HIV-1 reverse transcriptases mutated at codons 101 or 138. FEBS J 273(16):3850-3860.
  69. Romero-Ortega M, A Aviles, R Cruz, A Fuentes, RM Gomez, et al. (2000) Synthesis of 4-substituted 2-phenylaminothiazoles from amidines. a convenient route to 4-trichloromethylthiazoles. J. Org. Chem 65(21): 7244-7247.
  70. Rosli, MM, MS Karthikeyan, HK Fun, IA Razak, P. Patil (2006) N-(3-Chloro- 4-fluorophenyl) thiourea. Acta Crystallographica Section E: Structure Reports Online 63 (1):o67-o68.
  71. Roy KK, SSingh, SK Sharma, R Srivastava, V Chaturvedi,et al. (2011) Synthesis and biological evaluation of substituted 4-arylthiazol-2-amino derivatives as potent growth inhibitors of replicating Mycobacterium tuberculosis H37RV. Bioorg Med Chem Lett 21(18): 5589-5593.
  72. Ruppert J, W Welch, AN Jain (1997) Automatic identification and representation of protein binding sites for molecular docking. Protein Sci 6(3): 524-533.
  73. Saeed S, N Rashid, PG Jones, M Ali, R Hussain (2010) Synthesis, characterization and biological evaluation of some thiourea derivatives bearing benzothiazole moiety as potential antimicrobial and anticancer agents. Eur J Med Chem 45: 1323-1331.
  74. Sahu S, P Rani Sahoo, S Patel,B. Mishra (2011) Oxidation of thiourea and substituted thioureas: a review. J Sulphur Chem 32(2): 171-197.
  75. Saxena AK, SK Pandey, P Seth, M Singh, M Dikshit,et al. (2001) Synthesis and QSAR studies in 2-(N-aryl-N-aroyl) amino-4, 5-dihydrothiazole derivatives as potential antithrombotic agents. Bioorg Med Chem 9(8): 2025-2034.
  76. Schroeder DC (1955) Thioureas. Chemical Reviews 55(1): 181-228.
  77. Shearer BG, S Lee, JA Oplinger, LW Frick, EP Garvey, et al. (1997) Substituted N-phenylisothioureas: potent inhibitors of human nitric oxide synthase with neuronal isoform selectivity. J Med Chem 40(12): 1901-1905.
  78. Shi HB, WX Hu,YF Lin (2009) N-(3,4-Dichlorophenyl)thiourea. Acta Crystallographica Section E: Structure Reports Online 65(10): o2401.
  79. Shingare M, D Ingle (1977) Synthesis of some sulfonamide derivatives. J Indian Chem Soc 54: 705-708.
  80. Spallarossa A, S Cesarini, A Ranise, M Ponassi, T Unge, et al. (2008) Crystal structures of HIV-1 reverse transcriptase complexes with thiocarbamate nonnucleoside inhibitors. Biochem Biophys Res Commun 365 (4): 764-770.
  81. Spitzer R,AN. Jain (2012) Surflex-Dock: docking benchmarks and realworld application. J Comput Aided Mol Des 26 (6): 687-699.
  82. Stieber F, K Hellmuth, H Waldmann, R Mazitschek, A Giannis (2003) Preparation of 4-(hetero)aryl-substituted thia-, oxa-, and pyrazoles for inhibition of Tie-2: Kylix Pharmaceuticals BV, Neth.
  83. Thanigaimalai P, TA Le Hoang, KC Lee, SC Bang, VK Sharma,et al. (2010) Structural requirement(s) of N-phenylthioureas and benzaldehyde thiosemicarbazones as inhibitors of melanogenesis in melanoma B 16 cells. Bioorg Med Chem Lett 20(9): 2991-2993.
  84. Thanigaimalai P, KC Lee, VK Sharma, C Joo, WJ Cho,et al. (2011) Structural requirement of phenylthiourea analogs for their inhibitory activity of melanogenesis and tyrosinase. Bioorg Med Chem Lett 21(22): 6824-6828.
  85. Tisler M, Z Vrbaski (1960) Reaction of 4-arylthiosemicarbazides with some α-keto acids and synthesis of some substituted 3-thioxo-5-oxo-2, 3, 4, 5-tetrahydro- 1, 2, 4-triazines. J. Org. Chem 25(5): 770-773.
  86. Uckun FM, C Mao , S Pendergrass, D Maher, D Zhu,et al. (1999) N-[2-(1-Cyclohexenyl)ethyl]-N′-[2-(5-bromopyridyl)]- thiourea and N′-[2-(1-cyclohexenyl)ethyl]-N′-[2-(5- chloropyridyl)]-thiourea as potent inhibitors of multidrug-resistant human immunodeficiency virus-1. Bioorg Med Chem Lett 9(18): 2721-2726.
  87. Varshney K, S Gupta, N Rahuja, AK Rawat, N Singh,et al. (2012) Synthesis, structure-activity relationship and docking studies of substituted aryl thiazolyl phenylsulfonamides as potential protein tyrosine phosphatase 1B inhibitors. ChemMedChem 7(7): 1185-1190,
  88. Vig R, C Mao, T Venkatachalam, L Tuel-Ahlgren, EA Sudbeck,et al. (1998) Rational design and synthesis of phenethyl-5-bromopyridyl thiourea derivatives as potent non-nucleoside inhibitors of HIV reverse transcriptase. Bioorg Med Chem Lett 6(10): 1789-1797.
  89. Welch W, J Ruppert, AN Jain (1996) Hammerhead: fast, fully automated docking of flexible ligands to protein binding sites. Chem Biol 3(6): 449-462.
  90. Yadav PS, Devprakash D, Senthilkumar GP (2011) Benzothiazole: different methods of synthesis and diverse biological activities. International Journal of Pharmaceutical Sciences and Drug Research 3(1): 1-7.
  91. Yavari I, Z Hossaini, S Seyfi, F Shirgahi-Talari (2008) Efficient synthesis of functionalized thiazoles from acid chlorides, tetramethylthiourea, ethyl bromopyruvate, and ammonium thiocyanate. Helvetica Chimica Acta 91(6): 1177-1180.
  92. Yavari I, SZ Sayyed-Alangi, R Hajinasiri, H Sajjadi-Ghotbabadi (2009) A one-pot synthesis of functionalized ethyl 1, 3-thiazole-5-carboxylates from thioamides or thioureas and 2-chloro-1,3-dicarbonyl compounds in an ionic liquid. Monatshefte fur Chemie 140(2): 209-211.
  93. Yella R, V Kavala, BK Patel (2011) Bromineless bromine as an efficient desulfurizing agent for the preparation of cyanamides and 2-aminothiazoles from dithiocarbamate salts. Synth. Commun 41(6): 792-805.
  94. Zhang YM, TB Wei, LM Gao (2001) Synthesis and biological activity of N-aroyl-N′-substituted thiourea derivatives. Synth. Commun 31(20): 3099-3105.
  95. Zhao R, S Gove, JE Sundeen, BC Chen (2001) A new facile synthesis of 2-aminothiazole-5-carboxylates. Tetrahedron Lett. 42: 2101-2102.
  96. Meng G, He YP, Chen FE (2002) Three dimensional quantitative structureactivity relationship of HEPT analogues as HIV-1 reverse transcriptase inhibitors. Chemical Journal of Chinese Universities 23(7): 1304-1308.
  97. Meng G, Wang M, Shi JH, Yang T, Zheng ML, et al. (2011) A process for preparing ethyl 4-methyl-2-aminothiazole-5-carboxylate and its derivatives.

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