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Annals of Medicinal Chemistry and Research

Synthesis and In vitro Anti-Mycobacterial Activity Evaluation of Some Quinazolinyl Thioureido Scaffolds

Research Article | Open Access

  • 1. S. R. Rotary Institute of Chemical Technology, India
  • 2. Department of Chemistry, Veer Narmad South Gujarat University, India
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Corresponding Authors
Jigisha A Modi, S. R. Rotary Institute of Chemical Technology, Ankleshwar-Valia Road, Ta:Valia, Dist: Bharuch -393 002, Gujarat, India
Abstract

The current study reports design and diversity oriented synthesis of novel heterocycles incorporating of thioureido linkage on position no C-4 which not yet been explored and could find new applications in biology. Employing reagent based skeletal diversity approach; a facile synthesis of heterocycles with thioureido linkage at C-4 position of the quinazoline moiety has been accomplished. All the newly synthesized compounds were subjected to in vitro screening against various mycobacterial, bacterial and fungal strains. The bioassay results indicate some compounds could be emerged as the most promising anti tubercular and antimicrobial agents. All the intermediates and products have been isolated and fully characterized by IR, 1 H NMR and 13C NMR.

Citation

Modi JA, Patel KC (2016) Synthesis and In vitro Anti-Mycobacterial Activity Evaluation of Some Quinazolinyl Thioureido Scaffolds. Ann Med Chem Res 2(1): 1012.

Keywords

•    Quinazoline
•    Thioureido linkage
•    Minimum Inhibitory Concentration (MIC)
•    Antitubercular activity

INTRODUCTION

Discovery is the identification of novel active chemical compounds, often called “hits”, which are typically found by assay of compounds for a desired biological activity. Initial hits can come from repurposing existing agents toward new pathologic processes. Tuberculosis (TB) has been a leading cause of death since time immemorial and it continues to cause immense human misery even today. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration. In view of the fact there is need for the discovery of new, selective and promising inhibitor with an improved safety and efficacy profile has stimulated us to present an attractive approach towards design and development of new antimycobacterial scaffolds. Literature study reveals that more effectual new chemical scaffolds can be envisaged by incorporating two cyclic systems into a single molecule via linkage. With proven pharmacological significance, quinazolines have become a favourite field for many investigators and their efforts are quite significant in literature. According to recent data, quinazoline nucleus has attracted the attention of medicinal chemists due to its well known antifungal, anticancer & antitumor activity [1,2]. Quinazoline derivatives also known to show antibacterial and antitubercular activity [3,4]. This wide range of biological activities displayed by quinazolines is conferred by the diversity of the substituents that can be combined on the C-2,C-3 and C-6 centres. It is therefore of great interest to explore new type of substituent on the quinazoline ring in which incorporating of thioureido linkage on position C-4 which not yet been explored and could find new applications in biology.

Thioureas are of novel class of molecules found in many natural products. Their synthesis becomes a significant aspect in these days as many surrogates or substituents on the thiourea linkage may enhance its activity. In addition, thiourea compounds are associated with series of biological activities [5,6]. Thiourea are mimicking the urease in many functions; with growing application and versatile activity as active motif leads the chemists to make such thioureido [7] moieties. For these reasons synthesis of quinazoline moiety incorporated with thioureido linkage is of high interest. These novel compounds open up new perspectives in drug design by providing an entire range of highly specific, selective and non-toxic pharmaceuticals. Considering the advantage of biocompatibility and structural diversity of thiourea residues with the biological system, currently there is huge tendency of conjugating thiourea residues with bioactive heterocyclic motifs in the field of biomedical research. So here we designed synthetic route wherein the central key Quinazoline and different cyclic moieties built at C4 position employing diversity oriented synthesis.

R = 7a 4-NO2 , 7b 3-NO2 , 7c 2-NO2 , 7d 4-F, 7e 3-CH3 , 7f 2-Cl: 3-Cl, 7g 4-CH3 , 7h 4-OCH3 , 7i 2-Cl, 7j 3-Cl

Scheme 1. Reagents: a) HCONH2, 150°C b) PCl5 , POCl3, 115- 118o C c) IPA, K2 CO3, NH2 CH2 COOH, reflux 5-6 hrs. d) SOCl2 e) Acetone, NH4 NCS f) Acetone, sub. amine.

RESULTS AND DISCUSSION

Chemistry

The synthesis of the quinazolinyl thioureido unreported title compounds is as outlined in Scheme 1.In general, the basic strategy was the same as was used to make the lead structure; the combination of aromatic electrophilic and aromatic nucleophilic moieties corresponding to the target analogues. Hence in continuation of our work on quinazolines, we have incorporated thioureido linkage with quinazoline moiety. In this work, the lead structure, (6-nitroquinazolin-4(3h)-one) compound 2 was synthesized using the Niementowski cyclization according to the literature [8]. Compound 2 on reaction with phosphorous pentachloride and phosphorous oxychloride gave compound 3 which was synthesized according to literature [9]. Compound 3 on reaction with glycine gave quinazolinyl glycine derivative compound 4. The latter was then treated with thionyl chloride to produce compound 5 which on subsequent treatment with ammonium thiocyanate according to literature [10] gave compound 6 which on treatment with various aryl amines in acetone gave 7a-j. All the synthesized compounds were fully characterized by IR, 1 H-NMR, 13C NMR spectroscopy and elemental analysis.

The titled compounds were prepared through the reaction sequences depicted in Scheme 1. Compound 2 showed the presence of >NH group in IR (3170 cm-1) and 1 H NMR spectra which showed a broad signal around δ 7.17 (NH). The IR spectrum of compound 3 showed peak at 760 cm-1 for C-Cl. The IR spectrum of titled compound 7a showed peak at 1211 cm-1 (thioureido CS group) and its 1 H NMR spectrum showed a singlet at δ 8.62 (NHCSNH). In addition to that, the absence of a peak at 760 cm-1 for chloro group and presence of a peak at 1211 cm-1 (thioureido CS group) in compound 7a reveals that p-nitro phenyl thioureido linkage is present as a linker between phenyl ring and quinazoline moiety. The 13C NMR spectrum of 7a reveals carbon signals at δ 180.25, 169.29, 159.11 and 155.90 assigned to C=S, C=O, C2 and C4 , respectively.

Biological Activity

Antibacterial Activity:

1. Compounds

Test compounds were dissolved in DMF at an initial concentration of 40 mg\ ml and then were serially diluted in culture medium.

2. Cells

Bacterial strains: Staphylococcus aureus, Bacillus subtillis, Salmonella typhi, Klebsiella pneumonia

Fungal strain: Aspergillus niger

The minimum inhibitory concentrations (MICs) of the chemical compounds assays were carried out as described by Clause [11] with minor modifications. References viz., ampicillin trihydrate and ciprofloxacin (antibacterial agent) and fluconazole (antifungal agent) were used. Solutions of the test compounds and reference drugs were dissolved in DMF at a conc. of 20 mg ml-1. The two fold dilution of the compounds and reference drugs were prepared (40, 30, 20, 10, 05, etc.) mg ml-1. Antibacterial activities of the bacterial strains were carried out in Muller–Hinton broth (Difco) medium, at pH 6.9, with an inoculum of (1–2) × 103 cells ml-1 by the spectrophotometric method and an aliquot of 100 µl was added to each tube of the serial dilution. The chemical compounds–broth medium serial tube dilutions inoculated with each bacterium were incubated on a rotary shaker at 37°C for 24 h at 150 rpm. The MICs of the chemical compounds were recorded as the lowest concentration of each chemical compounds in the tubes with no growth (i.e.,no turbidity) of inoculated bacteria. The results obtained is summarized in Table 1.

Table 1 represents the antibacterial effect of the substituted quinazoline-4(3H)-ones and their thioanalogues. Two compounds of the obtained series owed high in vitro antimicrobial activity. Amongst the entire tested compounds, 7c showed excellent activity against S.Typhi and Kleb; 7f showed good activity against Bacillus subtillis and displayed excellent activity against fungus Aspergilus Niger.

Antitubercular Activity: All compounds 7(a-j) were screened at 62.5 µg/ml for their in vitro antimycobacterial activity against M. tuberculosis H37Rv strain using Lowenstein-Jensen medium method [12]. Positive and negative growth controls were run in each experiment and Rifampicin was used as standard drug.

The antitubercular effects of new synthesized compounds 7a-j were investigated against M. tuberculosis H37Rv strain and the results are shown in Figure 1. The compounds 7c (2- NO2 ), 7d (4-F) and 7i (2-Cl) possess elevated activity against M. tuberculosis H37Rv strain while all the remaining compounds possess moderate to poor efficiency.

CONCLUSION

A series of quinazoline moiety incorporated with thioureido linkage were successfully synthesized and screened for antimicrobial and antitubercular activity. It is seen from the biological screening result that the several quinazoline moiety incorporated with thioureido linkage were interestingly found to be more active than their corresponding precursors. The probable reason for such behaviour with Gram –ve is the ortho position of nitro group on the aromatic ring compared to Meta and para position. In addition to this the presence of more than one electron-donating group on the aromatic ring in general influences the antifungal activity compared to compounds with electron withdrawing groups. Besides this, presence and the position of thioureido (–NHCSNH-) group as the connecting linker between the aromatic ring and quinazoline ring seem to be very significant for antimicrobial effect. The tested compounds were found to be active against S.typhi, Kleb and A.niger as paralleled to standards. Antitubercular activity of some compounds was found good against M. tuberculosis H37Rv as compared to that of Rifampicin.

Table 1: Antimicrobial Activity.

Compound No. MIC in mM MIC in mM Antifungal Strains A. niger
Antibacterial Strains Antibacterial Strains
B. subtilis S. aureus S. typhi Kleb
7a 0.70 0.70 0.70 0.47 0.70
7b 0.70 0.70 0.70 0.70 0.47
7c 0.70 0.70 0.23 0.18 0.70
7d 0.74 0.50 0.50 0.75 0.50
7e 0.50 0.76 0.76 0.50 0.50
7f 0.44 0.66 0.66 0.44 0.44
7g 0.81 0.81 0.81 0.54 0.81
7h 0.72 0.72 0.72 0.73 0.72
7i 0.72 0.72 0.48 0.48 0.71
7j 0.72 0.72 0.48 0.72 0.71
Ampicillin 0.27 0.13 0.20 0.13 -
Ciprofloxacin 0.25 0.19 0.19 0.12 -
Fluconazole - - - - 0.35
Abbreviations: B. Subtilis-Bacillus Subtilis; S. Aureus-Staphylococcus Aureus; S. Typhi-Salmonella Typhi; Kleb- Klebsiella Pneumonia; A. NigerAspergillus Niger

 

EXPERIMENTAL

Reagents, Instrumentation and Measurements

All chemicals and solvents were of analytical grade and used directly. All the melting points were determined in open capillaries and are uncorrected. TLC analysis was done using precoated silica gel plates and visualization was done using iodine.

Apparatus

IR spectra (υmax in cm-1) were recorded on Nicolet is10 FTIR spectrophotometer using KBr pellets. 1 H NMR and 13C NMR spectra were recorded at 300 MHz and 75.5 MHz, respectively (Bruker Avance II), using DMSO as solvent and TMS as internal reference (chemical shifts in δ, ppm).The elemental analysis (C, H, N) of compounds were performed on Carlo Erba–1108 elemental analyzer. Their results were found to be in good agreement with the calculated values.

Synthesis of 6-nitroquinazolin-4(3h)-one (Compound 2)

A mixture of 5-Nitroanthranilic acid (0.01 mole) and formamide (20 ml) were heated for 8-10 hrs at 150-160o C under stirring with a magnetic stirrer. The mixture was then allowed to cool, and the precipitates were filtered off and dried at 80o C to give 6-nitro quinazolin-4(3H)-one (M.P.283-285°C)

Synthesis of 4-chloro-6-nitroquinazoline (Compound 3)

A mixture of 6-Nitro quinazoline-4(3H)-one (0.01mole), phosphorus pentachloride (0.05mole) and phosphorus oxychloride (16 ml) were heated and stirred under reflux for 8 hr at 115-118°C. Excess of phosphorus oxychloride was then removed by distillation. The residue obtained was acidified with sodium bicarbonate solution (5%w/v). The resulting precipitate was collected by filtration, washed with water, and dried to give 4-chloro-6-nitroquinazoline (M.P.220-223°C).

Synthesis of [(6-nitroquinazolin-4-yl) amino] acetic acid (compound 4)

A mixture of 4-Chloro-6-nitroquinazoline (0.01mole) and anhydrous K2 CO3 (0.02mole) were taken in isopropyl alcohol. To this drop wise addition of glycine (0.01mole) in IPA with continuous stirring was done for half an hour. Then the reaction mixture was refluxed for 5-6 hrs. After the completion of reaction (checked by TLC), reaction mixture was then poured over crushed ice. The resulting precipitate was neutralized by conc. HCl. The product was collected by filtration, washed with water and dried to give [(6-nitro quinazoline-4-yl) amino] acetic acid. (M.P.157-159°C).

Synthesis of n-[(substituted phenyl) carbamothioyl]- 2-[6-nitroquinazolin-4-yl) amino] acetamide (Compound 5,6 &7 )

A mixture of [(6-nitroquinazolin-4-yl) amino] acetic acid (0.01mole) and thionyl chloride (0.015mole) were refluxed for 3 hrs. Excess of thionyl chloride was distilled off. The product was then cooled and was dissolved in acetone (40 ml). Ammonium thiocyanate in acetone was then added slowly with constant stirring at room temperature. The reaction mixture was kept under reflux condition for 1 hr. Afterwards the solution of amine (0.01mole) in acetone was added slowly with constant stirring at room temperature. The reaction mixture was then refluxed for 3-4 hrs. The solution was poured into ice-cold water and the above product was recrystallized by using ethanol.

Spectral data of Compounds 7(a-j)

Compound (7a). Yield 67%, brown; mp 150 °C; Anal. Calcd for C17H13N7 O5 S (427.39): C, 47.77%; H, 3.07%; N, 22.94%. found: C, 47.54%; H, 2.58 %; N, 22.87%; IR (KBr)/cm-1: 3172 cm-1 (-NH- ), 1680 cm-1 (>C=O), 1615 cm-1 (-C=N-), 1211 cm-1 (C=S), 1339 cm-1 (-C-N), 1557,1283 cm-1 (-NO2 ); 1H NMR CDCl3: 4.28 (s, 2H, CH2 ), 7.11 (s, 1H, Ar-NH), 8.62 (s, 1H, CSNH), 9.08 (s, 1H, CONH), 7.30-8.11 (m, 8H, Ar-H);13C NMR (75.5 MHz, CDCl3 ): δ 180.25 (C=S), 169.29 (C=O), 159.11 (C=N, C2 ), 155.90 (C=N, C4 ), 151.54 (CHAr), 137.31 (CHAr), 134.58 (CHAr), 131.12 (CHAr), 129.84 (CHAr), 128.68 (CHAr), 127.79 (CHAr), 120.60 (CHAr), 118.79 (CHAr), 115.62 (CHAr), 112.58 (CHAr), 48.27 (NCH2 ).

Compound (7b). Yield 64%, yellow; mp 170 °C; Anal. Calcd for C17H13N7 O5 S (427.39): C, 47.77%; H, 3.07%; N, 22.94%. found: C, 47.57%; H, 2.86 %; N, 22.78%;IR (KBr)/cm-1: 3175 cm-1 (-NH- ), 1676 cm-1 (>C=O), 1612 cm-1 (-C=N-), 1210 cm-1 (C=S), 1334 cm-1 (-C-N), 1555,1281 cm-1 (-NO2 ); 1H NMR CDCl3: 4.31 (s, 2H, CH2 ), 7.09 (s, 1H, Ar-NH), 8.59 (s, 1H, CSNH), 9.09 (s, 1H, CONH), 7.28-8.12 (m, 8H, Ar-H); 13C NMR (75.5 MHz,CDCl3): δ 180.23 (C=S), 170.01 (C=O), 159.08 (C=N, C2 ), 155.87 (C=N, C4 ), 152.34 (CHAr), 137.05 (CHAr), 133.28 (CHAr), 130.08 (CHAr), 128.82 (CHAr),127.88 (CHAr), 126.19 (CHAr), 120.56 (CHAr), 118.58 (CHAr), 115.31 (CHAr), 113.80 (CHAr), 48.22 (NCH2 ).

Compound (7c). Yield 65%, yellow; mp 146 °C; Anal. Calcd for C17H13N7 O5 S (427.39): C, 47.77%; H, 3.07%; N, 22.94%. found: C 47.46%; H,2.86 %; N,22.75%; IR (KBr)/cm-1: 3198 cm-1 (-NH- ), 1684 cm-1 (>C=O), 1610 cm-1 (-C=N-), 1208 cm-1 (C=S), 1339 cm-1 (-C-N), 1560,1283 cm-1 (-NO2 ); 1H NMR CDCl3: 4.28 (s, 2H, CH2 ), 7.09 (s, 1H, Ar-NH), 8.63 (s, 1H, CSNH), 9.13 (s, 1H, CONH), 7.15-8.08 (m, 8H, Ar-H); 13C NMR (75.5 MHz,CDCl3 ): δ 180.15 (C=S), 169.75 (C=O), 159.16 (C=N, C2 ), 154.87 (C=N, C4 ), 152.56 (CHAr), 138.31 (CHAr), 134.28 (CHAr), 133.02 (CHAr), 130.62 (CHAr),129.68 (CHAr), 127.45 (CHAr), 121.60 (CHAr), 119.61 (CHAr), 114.62 (CHAr), 112.24 (CHAr), 48.25 (NCH2 )

Compound (7d). Yield 68%, brown; mp 200°C; Anal. Calcd for C17H13FN6 O3 S (400.38): C, 51.00%; H, 3.27%; N, 20.99%. found: C, 50.82%; H,3.11 %; N, 20.56%; IR(KBr)/cm-1: 3169 cm-1 (-NH-), 1684 cm-1 (>C=O), 1617 cm-1 (-C=N-), 1211 cm-1 (C=S), 1337 cm-1 (-C-N), 1559,1281 cm-1 (-NO2 ), 1132 cm-1 (C-F); 1H NMR CDCl3: 4.30 (s, 2H, CH2 ), 7.10 (s, 1H, Ar-NH), 8.60 (s, 1H, CSNH), 9.08 (s, 1H, CONH), 7.30-8.10 (m, 8H, Ar-H); 13C NMR (75.5 MHz, CDCl3 ): δ 180.14 (C=S), 169.62 (C=O), 158.43 (C=N, C2 ), 155.75 (C=N, C4 ), 152.04 (CHAr), 137.89 (CHAr), 135.56 (CHAr), 132.52 (CHAr), 130.64 (CHAr),128.68 (CHAr), 127.21 (CHAr), 121.93 (CHAr), 119.34 (CHAr), 115.12 (CHAr), 113.87 (CHAr), 48.19 (NCH2 ).

Compound (7e). Yield 70%, white; mp 238°C; Anal. Calcd for C18H16N6 O3 S (396.42): C, 54.54%; H, 4.07%; N, 21.20%. found: C, 54.26%; H,3.85 %; N, 21.01%; IR (KBr)/cm-1: 3185 cm-1 (-NH- ), 1661 cm-1 (>C=O), 1615 cm-1 (-C=N-), 1217 cm-1 (C=S), 1337 cm-1 (-C-N), 1558,1287 cm-1 (-NO2 ); 1H NMR CDCl3: 4.28 (s, 2H, CH2 ), 7.07 (s, 1H, Ar-NH), 8.54 (s, 1H, CSNH), 9.10 (s, 1H, CONH), 7.15-8.22 (m, 8H, Ar-H);13C NMR (75.5 MHz, CDCl3 ): δ 181.05 (C=S), 170.29 (C=O), 158.11 (C=N, C2 ), 156.90 (C=N, C4 ), 152.60 (CHAr), 138.51 (CHAr), 135.42 (CHAr), 132.02 (CHAr), 131.32 (CHAr),127.55 (CHAr), 126.79 (CHAr), 125.30 (CHAr), 120.52 (CHAr), 119.12 (CHAr), 113.70 (CHAr), 48.22 (NCH2 ).

Compound (7f). Yield 75%, white; mp 210°C; Anal. Calcd for C17H12Cl2 N6 O3 S (451.28): C, 45.24%; H, 2.68%; N, 18.62%. found: C, 45.21%; H,2.55 %; N, 18.52%; IR (KBr)/cm-1: 3177 cm-1 (-NH- ), 1672 cm-1 (>C=O), 1616 cm-1 (-C=N-), 1217 cm-1 (C=S), 1340 cm-1 (-C-N), 1557,1282 cm-1 (-NO2 ), 757 cm-1 (C-Cl); 1H NMR CDCl3: 4.31 (s, 2H, CH2 ), 7.08 (s, 1H, Ar-NH), 8.55 (s, 1H, CSNH), 9.05 (s, 1H, CONH), 7.11-8.27 (m, 7H, Ar-H); 13C NMR (75.5 MHz, CDCl3 ): δ 181.23 (C=S), 170.15 (C=O), 159.20 (C=N, C2 ), 155.45 (C=N, C4 ), 152.34 (CHAr), 137.92 (CHAr), 135.02 (CHAr), 132.15 (CHAr), 130.65(CHAr), 129.84 (CHAr), 127.79 (CHAr), 121.85 (CHAr), 120.58 (CHAr), 117.35 (CHAr), 112.58 (CHAr), 47.86 (NCH2 )

Compound (7g). Yield 67%, white; mp 190°C; Anal. Calcd for C18H16N6 O3 S (396.42): C, 54.54%; H, 4.07%; N, 21.20%. found: C, 54.40%; H,3.89 %; N, 21.02%; IR (KBr)/cm-1: 3195 cm-1 (-NH-), 1676 cm-1 (>C=O), 1614 cm-1 (-C=N-), 1205 cm-1 (C=S), 1328 cm-1 (-C-N), 1568,1277 cm-1 (-NO2 ); 1H NMR CDCl3: 4.30 (s, 2H, CH2 ), 7.09 (s, 1H, Ar-NH), 8.54 (s, 1H, CSNH), 9.11 (s, 1H, CONH), 7.21- 8.34 (m, 8H, Ar-H); 13C NMR (75.5 MHz, CDCl3 ): δ 181.25 (C=S), 170.19 (C=O), 160.31 (C=N, C2 ), 156.54 (C=N, C4 ), 151.54 (CHAr), 138.01 (CHAr), 135.32 (CHAr), 133.54 (CHAr), 130.84 (CHAr), 129.68 (CHAr), 128.79 (CHAr), 122.34 (CHAr), 120.67 (CHAr), 119.19 (CHAr), 113.51 (CHAr), 48.07 (NCH2 ).

Compound (7h). Yield 71%, white; mp 215 °C; Anal. Calcd for C18H16N6 O4 S (412.42): C, 52.42%; H, 3.91%; N, 20.38%. found: C, 52.25%; H,3.67 %; N, 20.16%; IR (KBr)/cm-1: 3184 cm-1 (-NH- ), 1672 cm-1 (>C=O), 1616 cm-1 (-C=N-), 1206 cm-1 (C=S), 1330 cm-1 (-C-N), 1568,1277 cm-1 (-NO2 ); 1H NMR CDCl3: 4.30 (s, 2H, CH2 ), 7.09 (s, 1H, Ar-NH), 8.53 (s, 1H, CSNH), 9.11 (s, 1H, CONH), 7.21-8.24 (m, 8H, Ar-H); 13C NMR (75.5 MHz, CDCl3 ): δ 180.31 (C=S), 170.62 (C=O), 160.45 (C=N, C2 ), 155.90 (C=N, C4 ), 152.32 (CHAr), 139.33 (CHAr), 135.53 (CHAr), 132.12 (CHAr), 130.52 (CHAr),128.40 (CHAr), 127.61 (CHAr), 119.60 (CHAr), 118.53 (CHAr), 114.62 (CHAr), 113.58 (CHAr), 48.12 (NCH2 ).

Compound (7i). Yield 68%, yellow; mp 160 °C; Anal. Calcd for C17H13ClN6 O3 S (416.84): C, 48.98%; H, 3.14%; N, 20.16%. found: C, 48.74%; H,3.01 %; N, 20.03%; IR (KBr)/cm-1: 3186 cm-1 (-NH-), 1679 cm-1 (>C=O), 1621 cm-1 (-C=N-), 1208 cm-1 (C=S), 1328 cm-1 (-C-N), 1570,1281 cm-1 (-NO2 ), 760 cm-1 (C-Cl); 1H NMR CDCl3: 4.32 (s, 2H, CH2 ), 7.13 (s, 1H, Ar-NH), 8.54 (s, 1H, CSNH), 9.12 (s, 1H, CONH), 7.17-8.38 (m, 8H, Ar-H),13C NMR (75.5 MHz, CDCl3 ): δ 180.27 (C=S), 169.65 (C=O), 160.21 (C=N, C2 ), 156.55 (C=N, C4 ), 152.54 (CHAr), 137.31 (CHAr), 135.46 (CHAr), 131.80 (CHAr), 129.84 (CHAr), 128.32 (CHAr), 127.60 (CHAr), 119.25 (CHAr), 118.90 (CHAr), 114.62 (CHAr), 112.58 (CHAr), 48.20 (NCH2 ).

Compound (7j). Yield 70%, yellow; mp 200°C; Anal. Calcd for C17H13ClN6 O3 S (416.84): C, 48.98%; H, 3.14%; N, 20.16%. found: C,48.81%; H,2.89 %; N, 20.01%; IR(KBr)/cm-1: 3189 cm-1 (-NH-), 1675 cm-1 (>C=O), 1618 cm-1 (-C=N-), 1210 cm-1 (C=S), 1325 cm-1 (-C-N), 1573,1287 cm-1 (-NO2 ), 762 cm-1 (C-Cl); 1H NMR CDCl3: 4.29 (s, 2H, CH2 ), 7.10 (s, 1H, Ar-NH), 8.50 (s, 1H, CSNH), 9.08 (s, 1H, CONH), 7.13-8.27 (m, 8H, Ar-H),13C NMR (75.5 MHz, CDCl3 ): δ 181.22 (C=S), 169.32 (C=O), 160.62 (C=N, C2 ), 156.20 (C=N, C4 ), 152.90 (CHAr), 138.35 (CHAr), 135.18 (CHAr), 133.02 (CHAr), 128.86 (CHAr), 128.20 (CHAr), 126.19 (CHAr), 121.35 (CHAr), 120.58 (CHAr), 119.79 (CHAr), 113.70 (CHAr), 48.36 (NCH2 ).

ACKNOWLEDGEMENTS

The authors are thankful to the Department of Chemistry, V. N. S. G. University, Surat, for laboratory and some analytical facilities. The authors also thankful to Bioscience department, V. N. S. G. University, Surat and Biogenics, Research & Training Centre in Biotechnology, Karnataka for Biological screening. The author are grateful to SAIF, Chandigarh and CDRI, Lucknow for analytical facilities.

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Received : 18 Jul 2015
Accepted : 31 Aug 2015
Published : 02 Sep 2015
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ISSN : 2578-3211
Launched : 2016
Journal of Human Nutrition and Food Science
ISSN : 2333-6706
Launched : 2013
JSM Regenerative Medicine and Bioengineering
ISSN : 2379-0490
Launched : 2013
JSM Spine
ISSN : 2578-3181
Launched : 2016
Archives of Palliative Care
ISSN : 2573-1165
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
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