alexa One-Pot Synthesis of Novel Substituted Phenyl-1,5-dihydro-2Hbenzo[ 4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine Derivatives as Potent Antimicrobial Agents

ISSN: 2161-0444

Medicinal Chemistry

  • Research Article   
  • Med chem (Los Angeles) 2018, Vol 8(1): 001
  • DOI: 10.4172/2161-0444.1000488

One-Pot Synthesis of Novel Substituted Phenyl-1,5-dihydro-2Hbenzo[ 4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine Derivatives as Potent Antimicrobial Agents

Talavara Venkatesh1, Yadav D Bodke1*, Nagaraj K2 and Ravi Kumar S3
1Department of PG Studies and Research in Chemistry, Jnana Sahyadri, Kuvempu University, Shankaraghatta, Shivamogga, Karnataka, India
2Department of PG Studies and Research in Microbiology, Jnana Sahyadri, Kuvempu University, Shankaraghatta, Shivamogga, Karnataka, India
3Department of PG Studies and Research in Biotechnology, Jnana Sahyadri, Kuvempu University, Shankaraghatta, Shivamogga, Karnataka, India
*Corresponding Author: Yadav D Bodke, Department of PG Studies and Research in Industrial Chemistry, Jnana Sahyadri, Kuvempu University, Shankaraghatta, Shivamogga, Karnataka, India, Tel: +919449140275, Email: [email protected]

Received Date: Jan 01, 2018 / Accepted Date: Jan 22, 2018 / Published Date: Jan 27, 2018

Abstract

In this paper, we have reported the synthesis of novel substituted phenyl-1,5-dihydro-2H-benzo[4,5] thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine derivatives (4a-m). The title compounds were synthesized by the reaction of substituted 2-aminobenzothiazole, barbituric/thiobarbituric acid and substituted benzaldehydes using 2-3 drops of HCl in ethanol. The synthesized compounds were evaluated for their antimicrobial efficiency against various microbial strains at different concentrations. Among the tested compounds, the compounds 4k and 4j were found to be more active against all the tested pathogens. Additionally, selected compounds were screened for in silico molecular docking studies.

Keywords: Condensation; Pyrimidine; Antimicrobial activity; Molecular docking study

Introduction

Multicomponent reactions (MCR) play an important role in organic, combinatorial and medicinal chemistry [1] as it furnishes products with a high degree of chemical and structural variability. Their productivity and the simplicity of reaction techniques make MCRs inexpensive, less time-consuming and ecofriendly in comparison to conventional multistep synthesis [2,3]. The exploitation of a simple molecule with various functionalities for the synthesis of bio heterocycles is a useful contribution in the heterocyclic chemistry [4]. Recently, the chemistry and biological outlines of several pharmacophores of 2-substituted benzothiazole products have been addressed [5,6]. The effect of substituents on the benzothiazole ring displayed accompanying structure-activity relationship [7]. Furthermore, benzothiazole derivatives are essential scaffolds in drug design associated with broad verities of medicinal uses [8]. On the other hand, pyrimidine is also a familiar class of heterocyclic compound possessing a wide range of biological activities and their importance in medicine is very much recognized [9]. Several pyrimidine derivatives have exhibited efficiency in fighting various diseases and observed to use as good beneficial agents such as antibacterial [10], antifungal [11], anti-tumor [12] and anti-HIV agents [13].

Encouraged by the above results, in this paper we have reported the synthesis of some novel substituted phenyl-1,5-dihydro-2H-benzo[4,5] thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine derivatives. All the newly synthesized compounds were screened for the in vitro antimicrobial activities. In addition, we described the analysis of potentially active target compounds against DNA Gyrase and CYP51 ligands by comparing the various docked orientations of the molecules.

Experimental Section

Materials and methods

All reactions were performed at reflux temperature with stirring, the chemicals were purchased from Merck and solvents were used without further purification. Analytical thin layer chromatography was performed with E. Merck silica gel GF254 glass plates and melting point was determined using thermal analyzer (Shimadzu DS-50). The FTIR spectra were obtained using KBr pellets on Shimadzu spectrometer, the 1H-NMR and 13C-NMR spectrum were recorded on Bruker 400 MHz and 100 MHz respectively in DMSO-d6 as a solvent using tetramethylsilane (TMS) as internal standard. LCMS were obtained using C-18 column on Shimadzu, LCMS 2010A, Japan.

General procedure for synthesis of substituted phenyl-1,5-dihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimido[4,5-d] pyrimidine derivatives (4a-m)

The mixture of substituted 2-aminobenzothiazoles (1 mmol), barbituric/thiobarbituric acid (1 mmol), substituted benzaldehydes (1 mmol) and 2-3 drops of HCl in ethanol was refluxed with constant stirring for about 8 h. After completion of the reaction, the reaction mixture was poured into the crushed ice with vigorous stirring and the solid residue separated was filtered, dried and recrystallized using ethanol.

5-(4-Hydroxyphenyl )-1,5-d ihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine-2,4(3H)-dione (4a): Pale yellow; yield 91%; mp 308-310°C; IR (cm-1): 1593, 1666, 2916, 3266, 3431; 1H-NMR (DMSO-d6) δ ppm: 5.89 (s, 1H, N-CH), 6.83-8.28 (m, 8H, Ar-H), 9.44 (s, 1H, Ar-OH), 11.33 (s, 1H, NH), 11.41 (s, 1H, NH); 13C-NMR (DMSO-d6) δ ppm: 61.85, 119.41, 121.78, 123.47, 125.25, 126.06, 126.94, 134.33, 136.54, 147.25, 149.60, 155.05, 157.91, 161.51, 168.52; LCMS: m/z [M+1]: 365.00.

5-(3-Fluorophenyl)-1,5-dihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine-2,4(3H)-dione (4b): Light yellow; yield 88%; mp 262-264°C; IR (cm-1): 752, 1597, 1643, 3249; 1H-NMR (DMSO-d6) δppm: 5.99 (s, 1H, N-CH), 6.15-8.22 (m, 8H, Ar-H), 11.52 (s, 1H, NH), 11.61 (s, 1H, NH); 13C-NMR (DMSO-d6) δppm: 61.87, 113.10, 118.77, 121.47, 122.94, 124.26, 125.51, 126.02, 126.17, 129.25, 134.01, 136.21, 146.66, 148.92, 157.31, 161.87, 164.92, 166.13; LCMS: m/z [M+1]: 367.00.

5-(3-Nitrophenyl)-1,5-dihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine-2,4(3H)-dione (4c): Dark yellow; yield 90%; mp 300-302°C; IR (cm-1): 1600, 1655, 3215; 1H-NMR (DMSO-d6) δppm: 5.98 (s, 1H, N-CH), 7.79-6.69 (m, 8H, Ar-H), 11.45 (s, 1H, NH), 11.57 (s, 1H, NH); 13C-NMR (DMSO-d6) δppm: 60.05, 100.12, 119.15, 124.47, 124.56, 126.51, 12.02, 128.17, 129.25, 133.08, 137.01, 147.08, 148.88, 155.34, 157.33, 163.22, 167.12; LCMS: m/z [M+1]: 395.03.

9-Chloro-5-(3-nitrophenyl)-2-thioxo-1,2,3,5-tetrahydro-4Hbenzo[4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidin-4-one (4d): Light brown; yield 88%; mp 293-295°C; IR (cm-1): 782, 1365, 1610, 1640, 3255; 1H-NMR (DMSO-d6) δppm: 5.58 (s, 1H, N-CH), 6.29- 7.82 (m, 7H, Ar-H), 11.62 (s, 1H, NH), 11.71 (s, 1H, NH); 13C-NMR (DMSO-d6) δppm: 59.55, 102.10, 118.10, 124.40, 124.65, 126.50, 127.82, 128.37, 129.45, 133.18, 137.51, 147.58, 148.62, 154.30, 157.20, 163.02, 167.18; LCMS: m/z [M+1] and [M+2]: 443 and 445.

9-Chloro-5-(3-fluorophenyl)-2-thioxo-1,2,3,5-tetrahydro-4Hbenzo[4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidin-4-one (4e): Light brown; yield 85%; mp 293-295°C; IR (cm-1): 756, 788, 1610, 1667, 3205; 1H-NMR (DMSO-d6) δppm: 5.89 (s, 1H, N-CH), 6.15- 8.28 (m, 7H, Ar-H), 11.50 (s, 1H, NH), 11.61 (s, 1H, NH); 13C-NMR ((DMSO-d6) δppm: 55.85, 98.07, 112.18, 122.47, 123.24, 124.36, 125.21, 126.22, 126.47, 129.22, 135.01, 136.26, 147.18, 148.82, 157.21, 160.82, 164.32, 167.24; LCMS: m/z [M+1] and [M+2]: 416 and 418.

9-Chloro-5-(2,6-difluorophenyl)-2-thioxo-1,2,3,5-tetrahydro-4H-benzo[4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidin-4-one (4f): Yellow; yield 83%; mp 256-258°C; IR (cm-1): 756, 788, 1610, 1647, 3205; 1H-NMR (DMSO-d6) δppm: 5.89 (s, 1H, N-CH), 6.15-8.28 (m, 6H, Ar- H), 11.33 (s, 1H, NH), 11.41 (s, 1H, NH); 13C-NMR (DMSO-d6) δppm: 54.83, 100.04, 111.16, 123.24, 124.36, 125.71, 126.42, 126.36, 132.22, 135.81, 136.86, 147.08, 148.62, 157.31, 161.12, 164.32, 167.24; LCMS: m/z [M+1] and [M+2]: 434.80 and 436.10.

9-Chloro-5-(4-hydroxyphenyl)-2-thioxo-1,2,3,5-tetrahydro-4Hbenzo[4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidin-4-one (4g): Dark orange; yield 90%; mp 310-312°C; IR (cm-1): 785, 1335, 1610, 1641, 3260, 3448; 1H-NMR (DMSO-d6) δppm: 5.30 (s, 1H, N-CH), 6.82-8.27 (m, 7H, Ar-H), 9.53 (s, 1H, OH), 11.33 (s, 1H, NH), 11.41 (s, 1H, NH); 13C-NMR (DMSO-d6) δppm: 60.05, 96.29, 119.01, 121.88, 123.07, 125.26, 126.16 (2C), 126.96, 134.13, 138.04, 147.35, 149.20, 155.55, 162.23, 157.82, 162.01, 169.02; LCMS: m/z [M+1] and [M+2]: 415.10 and 417.00.

5-(4-Chlorophenyl)-1,5-dihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine-2,4(3H)-dione (4h): Light gray; yield 86%; mp 290-292°C; IR (cm-1): 784, 1605, 1658, 1678, 3218; 1H-NMR (DMSO-d6) δppm: 5.96 (s, 1H, N-CH), 6.84-8.30 (m, 8H, Ar-H), 11.02 (s, 1H, NH), 11.11 (s, 1H, NH); 13C-NMR (DMSO-d6) δppm: 65.24, 96.00, 113.11, 123.28, 124.10, 127.82, 128.37, 129.45, 134.12, 138.21, 148.18, 149.60, 155.20, 157.25, 162.23, 168.10; LCMS: m/z [M+1] and [M+2]: 383.02 and 385.03.

5-(P-tolyl)-1,5-dihydro-2H-benzo[4,5]thiazolo[3,2-a] pyrimido[4,5-d]pyrimidine-2,4(3H)-dione (4i): Light white; yield 90%; mp 285-287°C; IR (cm-1): 1610, 1652, 3220; 1H-NMR (DMSO-d6) δppm: 2.43 (s, 3H, CH3), 5.98 (s, 1H, N-CH), 6.80-8.32 (m, 8H, Ar- H), 11.10 (s, 1H, NH), 11.22 (s, 1H, NH); 13C-NMR (DMSO-d6) δppm: 21.18, 63.28, 95.02, 114.10, 123.15, 124.36, 126.23, 127.30, 128.32, 129.46, 135.10, 138.01, 147.14, 148.90, 155.30, 157.05, 167.18; LCMS: m/z [M+1]: 363.06.

5-Phenyl-1,5-dihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine-2,4(3H)-dione (4j): Light gray; yield 85%; mp 248-250°C; IR (cm-1): 1615, 1720, 1678, 3240; 1H-NMR (DMSO-d6) δppm: 5.93 (s, 1H, N-CH), 6.76-8.30 (m, 9H, Ar-H), 11.12 (s, 1H, NH), 11.20 (s, 1H, NH); 13C-NMR (DMSO-d6) δppm: 61.20, 94.08, 113.18, 122.10, 123.66, 126.22, 128.62 130.16, 136.12, 139.09, 148.10, 149.50, 156.35, 158.08, 162.23, 168.10; LCMS: m/z [M+1]: 349.06.

5-Phenyl-2-thioxo-1,2,3,5-tetrahydro-4H-benzo[4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidin-4-one (4k): Light yellow; yield 88%; mp 276-278°C; IR (cm-1): 1618, 1542, 1644, 3245(NH); 1H-NMR (DMSO-d6) δppm: 5.96 (s, 1H, N-CH), 6.78-8.32 (m, 9H, Ar-H), 11.24 (s, 1H, NH), 11.33 (s, 1H, NH); 13C-NMR (DMSO-d6) δppm: 65.28, 98.48, 113.25, 123.10, 124.60, 126.23, 128.65, 129.12, 135.13, 138.29, 147.20, 148.20, 157.33, 158.56, 162.22, 168.20; LCMS: m/z [M+1]: 365.40.

2-Thioxo-5-(p-tolyl)-1,2,3,5-tetrahydro-4H-benzo[4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidin-4-one (4l): Light yellow; yield 90%; mp 326-328°C; IR (cm-1): 1545, 1620, 1671, 3255; 1H-NMR (DMSO-d6) δppm: 2.43 (s, 3H, CH3), 5.96 (s, 1H, N-CH), 6.78-8.32 (m, 9H, Ar-H), 11.03 (s, 1H, NH), 11.11 (s, 1H, NH); 13C-NMR (DMSO-d6) δppm: 22.24, 64.25, 95.43, 113.05, 123.36, 124.62. 125.26, 128.86, 130.54, 135.16, 138.23, 147.00, 148.28, 156.96, 158.88, 163.45, 169.24; LCMS: m/z [M+1]: 379.06.

5-(4-Chlorophenyl)-2-thioxo-1,2,3,5-tetrahydro-4H-benzo[4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidin-4-one (4m): Pale yellow; yield 88%; mp 288-290°C; IR (cm-1): 785, 1343, 1614, 1658, 3240; 1H-NMR (DMSO-d6) δppm: 5.99 (s, 1H, N-CH), 6.75-8.35 (m, 8H, Ar-H), 11.10 (s, 1H, NH), 11.22 (s, 1H, NH); 13C-NMR (DMSO-d6) δppm: 66.32, 108.23, 112.03, 124.06, 125.02, 126.36, 128.23, 129.04, 133.56, 137.07, 146.05, 147.88, 155.16, 157.54, 163.43, 169.14; LCMS: m/z [M+1] and [M+2]: 398 and 400.01.

Antimicrobial activity

The synthesized compounds were screened for in vitro antimicrobial activity against five pathogenic bacterial strains viz., Escherichia coli (MTCC 1559), Pseudomonas syringae (MTCC-1604), Salmonella typhi (MTCC-734), Staphylococcus aureus (MTCC-902) and Xanthomonas campestris (MTCC-2286) and five fungal strains, Alternaria solani (MTCC-2101), Aspergillus flavus (MTCC-277), Fusarium oxysporum (MTCC-284), Candida albicans (MTCC-1637) and Chrysosporium keratinophilum (MTCC-1367).

The in vitro antimicrobial activity was determined by agar well diffusion method [14]. The 10% DMSO was used as a negative control whereas ciprofloxacin was used as standard for antibacterial activity and bavistin for antifungal activity. The Minimum Inhibitory Concentration (MIC) measurements were achieved by using serial broth-dilution method [15].

In silico molecular docking studies

The structure of synthesized molecules and standards were drawn in Chem Bio Draw tool (Chem Bio Office Ultra 14.0 suite) assigned with proper 2D orientation and structure of each was checked for structural drawing error. Energy of each molecule was minimized using Chem Bio 3D (Chem Bio Office Ultra 14.0 suite). The energy minimized ligand molecules were then used as input for Auto Dock Vina, in order to carry out the docking simulation. The protein data bank (PDB) coordinate file with the name DNA Gyrase and CYP51 was used as receptor molecule in antibacterial and antifungal activity respectively [16,17].

Results And Discussion

Chemistry

In the present study, the synthesis of target compounds was achieved according to the reaction illustrated in the Scheme 1. The novel substituted phenyl-1,5-dihydro-2H-benzo[4,5]thiazolo[3,2-a] pyrimido[4,5-d]pyrimidine derivatives (4a-m) were synthesized via the one pot three component condensation reaction between 2-amino benzothiazole, barbituric/thiobarbituric acid and substituted benzaldehyde in ethanol using hydrochloric acid as a catalyst at reflux temperature with constant stirring.

The structure of the desired substituted phenyl-1,5-dihydro-2Hbenzo[ 4,5]thiazolo[3,2-a]pyrimido[4,5-d]pyrimidine derivatives (4a-m) were confirmed by IR, NMR and Mass spectral data. The IR spectrum of compound 4a showed broad peak at 3431 cm-1 due to hydroxyl group and another band in the region 3266 cm-1 that corresponded to NH functionality. The absorption bands at 1666 and 1593 cm-1 corresponded C=O and C=N group respectively. The 1H-NMR spectrum of compound 4a exhibited two singlets at δ 11.33 and 11.41 ppm corresponded for two NH protons and another singlet at δ 9.44 ppm which confirmed the presence of OH proton. The multiplet between δ 8.28-6.84 ppm is due to aromatic protons and a singlet at δ 5.89 ppm corresponds to pyrimidine CH proton. Further, 13C-NMR spectrum of compound 4a confirmed the proposed structure by appearance of signal at δ 168.52 ppm due to the C=O carbon and another signal at δ 161.51 ppm correspond to C=N carbon of barbituric acid ring. Another signal at δ 157.91 ppm attributed to C-OH carbon. The mass spectrum of compound 4a showed molecular ion peak [M+] at m/z 365.00 which corresponds to the molecular weight of the compound 4a.

In vitro antimicrobial activity

All the tested samples showed appreciable antibacterial activity against the tested pathogens at 1, 2.5 and 5 mg/mL concentrations. The highest zone of inhibition was observed by compound 4j followed by 4d, 4e and 4k (Table 1).

Compound
Conc in mg/mL
Zone of inhibition in mm
S.a S.t P.s X.c E.c
1.0 2.5 5.0 1.0 2.5 5.0 1.0 2.5 5.0 1.0 2.5 5.0 1.0 2.5 5.0
4a 14 18 23 0 10 18 7 13 18 7 13 19 0 0 0
4b 14 18 23 11 16 22 0 8 14 8 15 17 7 18 23
4c 14 20 25 15 21 24 7 13 20 9 12 14 17 20 24
4d 14 21 28 16 20 24 7 14 21 9 13 15 18 21 25
4e 9 14 21 18 21 27 9 15 23 7 11 16 12 17 22
4f 18 20 24 9 12 20 8 13 17 8 14 18 18 19 24
4g 17 21 28 11 17 21 7 12 16 8 15 19 14 18 25
4h 11 18 25 0 10 16 0 6 13 9 16 20 14 18 23
4i 9 14 21 10 15 20 0 7 14 7 13 15 15 24 28
4j 19 24 30 11 18 24 7 15 19 8 12 17 11 15 24
4k 11 18 24 12 19 25 6 14 24 9 15 20 11 18 21
4l 11 14 20 14 19 22 0 8 14 8 13 18 16 20 25
4m 11 15 21 10 18 24 0 7 13 7 12 17 18 20 26
Ciproflaxin 14 18 32 16 23 30 15 20 29 14 21 32 18 25 35

S.a- Staphylococcus aureus; S.t- Salmonella typhi; P.s- Pseudomonas syringae; X.c- Xanthomonas campestris; E.c- Escherichia coli

Table 1: Antibacterial activity results of synthesized compounds (4a-m).

Similarly, the tested samples were screened for their antifungal activity and they showed appreciable inhibitory activity against the tested pathogens. The compounds 4i, 4e and 4m exhibited remarkable antifungal activity compared to other compounds (Table 2).

Compound Zone of inhibition in mm
Conc in A.s A.f F.o C.a C.k
mg/mL 1.0 2.5 5.0 1.0 2.5 5.0 1.0 2.5 5.0 1.0 2.5 5.0 1.0 2.5 5.0
4a 7 11 14 7 14 21 0 7 14 7 13 19 7 10 15
4b 7 13 15 7 13 22 7 13 20 8 15 17 0 7 13
4c 7 11 14 7 11 22 5 7 11 9 12 14 7 12 15
4d 7 12 14 7 12 24 0 6 12 9 13 15 7 11 16
4e 8 11 16 8 11 21 7 12 23 7 11 16 9 13 17
4f 9 14 13 9 12 20 0 7 13 8 14 18 8 12 17
4g 8 10 15 8 15 24 7 13 24 8 15 19 7 12 16
4h 9 12 14 9 14 25 0 6 13 9 16 20 0 7 14
4i 9 11 15 9 15 20 0 7 14 7 13 15 0 7 13
4j 7 12 16 7 14 24 7 13 21 8 12 17 7 14 18
4k 6 9 14 6 12 23 0 7 14 9 15 20 6 11 19
4l 7 11 15 7 13 24 9 15 26 8 13 18 0 7 14
4m 7 12 17 7 13 25 0 7 13 7 12 17 9 14 20
Bavistin 14 19 25 11 16 29 9 15 26 11 18 29 10 18 29

A.s- Alternaria solani; A.f- Aspergillus flavus ; F.o- Fusarium oxysporum; C.a- Candida albicans; C.k- Cryzosporium keratinophilum

Table 2: Antifungal activity results of synthesized compounds (4a-m).

The synthesized compounds were also subjected for the MIC study and the results are displayed in Table 3. Among all the compounds, compound 4k and 4j were found to be more effective against E. coli, P. syringae and S. aureus with MIC value of 50 μg/mL. The compounds 4d, 4e, 4f, 4g, 4h, 4i and 4l showed good potencies with MIC value in the range of 75-250 μg/mL against all the bacterial strains.

Compound Minimum inhibitory concentration (µg/mL)
S.a S.t P.s X.c E.c A.s A.f F.o C.a C.k 
4a 200 250 350 350 250 300 400 500 500 1000
4b 250 200 200 200 300 300 300 500 500 500
4c 150 100 200 250 300 400 500 500 500 1000
4d 100 200 250 250 100 250 300 400 400 500
4e 150 100 100 100 75 300 400 500 500 1000
4f 150 150 200 250 200 400 400 500 500 1000
4g 100 150 200 250 200 400 200 400 500 500
4h 100 200 150 200 100 300 150 300 250 400
4i 150 100 200 200 150 300 500 500 400 500
4j 50 100 200 200 50 150 150 150 400 400
4k 150 150 50 100 50 200 300 300 250 500
4l 200 250 200 250 150 250 250 150 300 400
4m 150 250 300 300 200 150 250 250 400 350
Ciproflaxin 25 75 25 75 50 --- --- --- --- ---
Bavistin --- --- --- --- --- 100 100 150 200 300

S.a- Staphylococcus aureus; S.t- Salmonella typhi; P.s- Pseudomonas syringae; X.c- Xanthomonas campestris; E.c- Escherichia coli; A.s- Alternaria solani; A.f- Aspergillus flavus; F.o- Fusarium oxysporum; C.a- Candida albicans; C.k- Cryzosporium keratinophilum

Table 3: Minimum antimicrobial concentration of synthesized compounds (4a-m).

Among all the compounds screened for antifungal efficacy, compounds 4j, 4h and 4m were found to have good MIC value of 150 μg/mL against F. oxysporum, A. flavus and A. solani respectively. The compounds 4d, 4e, 4f, 4g, 4i and 4l displayed considerable activity with MIC value in the range of 200-500 μg/mL against all the fungal strains.

The obtained results revealed that, human pathogenic bacteria E. coli, S. aureus and S. typhi were more susceptible to all the tested compounds and these results were in agreement with the findings of Sahu et al. [18]. The plant pathogens viz, A. flavus and F. oxysporum were more susceptible to tested compounds and X. campestris, P. syringae were found to be less susceptible [19]. All the compounds showed appreciable antimicrobial activity and the activity was comparable with the standard drugs ciprofloxacin and bavistin.

In silico molecular docking studies

The docking of receptors DNA Gyrase and CYP51 with synthesized compounds 4c, 4e, 4f, 4g, 4h, 4j and 4k exhibited well-established bonds with amino acids (Asp437, Arg1122, Ser1085, His470, Val312, Lys152, Gly311 and Tyr141 respectively) in the receptor active pocket. The synthesized molecules having 2D structure were converted to energy minimized 3D structures and were further used for in silico protein-ligand docking. Figures 1 and 2 (2D and 3D image) showed the docked images of synthesized molecules including standard drugs ciprofloxacin and bavistin. All the compounds showed appreciating results with encouraging binding energy and exhibited the bonding with one or other amino acids in the active pockets. In silico studies revealed that all the synthesized molecules showed good binding energy with strong affinity towards the target protein DNA Gyrase and CYP51 ranging from -5.1 to -5.9 kcal/mol and -9.0 and -9.6 respectively (Tables 4 and 5).

medicinal-chemistry-synthesized

Figure 1: Interaction of synthesized molecules 4c, 4f, 4e, 4g, 4h, 4k, 4j and Ciprofloxacin with DNA Gyrase.

medicinal-chemistry-synthesized-molecules

Figure 2: Interaction of synthesized molecules 4c, 4f, 4e, 4g, 4h, 4k, 4j and Bavistin with CYP51.

Compound Affinity (kcal/mol) H-bonds H-bond length (Å) H-bond with Hydrophobic Interactions
4c -5.9 2 2.98
3.11
2XCT:Asp437 ::4c:NAD
2XCT:Arg1122 ::4c:
Asp437, Arg458, Gly459, Ser1084, Phe1123
4e -5.3 2 3.09
3.20
2XCT:Asp437 ::4e:NAD
2XCT:Asp437 ::4e:NAJ
Gly436, Arg458, Gly459, Asp512, Arg1122
4f -5.1 0 - - Gly436, Asp437, Asp512, Ser1084, Arg1122, Phe1123
4g -5.5 2 3.18
3.18
2XCT:Asp437 ::4g:NAJ
2XCT:Arg1122 ::4g:OBA
Gly436, Arg458, Gly459, Asp512, Ser1084
4h -5.6 3 2.82
3.09
3.09
2XCT:Ser1085 ::4h:NAE
2XCT:Ser1085 ::4h:OAY
2XCT:Ser1084 ::4h:OAX
Gly436, Asp437, Gly459, Gly1082, Phe1123
4j -5.4 3 2.90
3.07
3.12
2XCT:Ser1085 ::4j:NAE
2XCT:Ser1085 ::4j:OAY
2XCT:Ser1084 ::4j:OAX
Gly436, Asp437, Gly459, Gly1082
4k -5.1 1 3.04 2XCT:Asp437 ::4k:NAD Arg458, gly459, Ser1084, Phe1123
Ciprofloxacin -4.4 1 3.04 2XCT:Arg1122 :: CIPROFLOXACIN:OAQ Asp512, Ser1084, Ser1085

Table 4: Docking results for antibacterial activity of synthesized compounds (4a-m).

Compound Affinity (kcal/mol) H-bonds H-bond length (Å) H-bond with Hydrophobic interactions
4c -9.6 2 3.01
3.10
5JLC:His470::4c:NAD
5JLC:His470::4c:NAJ
Phe135, Ile140, Tyr141, Lys152, Phe237, Gly311, Val312, Met314, Gly315, Phe465, Cys472
4e -9.6 0 - - Tyr127, Tyr141, Phe242, Leu381, Leu384, Arg386, His 470
4f -10.0 1 3.03 5JLC:Val312::4f:NAE Thr131, Ile140, Leu148, Lys152, Phe237, Gly311, Gly315, Gly316, Leu381, Ile472, Cys472
4g -9.6 1 3.17 5JLC:Lys152::4g:OBA Thr131, Phe135, Ile140, Tyr141, Leu148, Val155, Leu159, Val312, Gly315, His470, Cys472, Ile473, Gly474
4h -9.3 2 2.93
2.96
5JLC:His470::4h:NAD
5JLC:His470::4h:NAJ
Thr131, Ile140, Tyr141, Leu148, Lys152, Phe237, Gly311, Val312, Gly315, Phe465, Arg471, Cys472
4j -9.0 2 3.31
3.35
5JLC:Gly311::4j:NAJ
5JLC:Gly311::4j:NAD
Tyr127, Phe135, Ile140, Tyr141, Leu148, Lys 152, Val312, Gly315, His470, Cys472
4k -9.0 1 2.91 5JLC:Tyr141::4k:OAX Phe114, Tyr127, Gly311, Val312, Gly315, Leu381, Leu384, Arg386, Phe465, His470, Cys472
Bavistin -7.1 3 2.78
3.12
3.21
5JLC:Ser383::BAVISTIN:NAJ
5JLC:Ser383::BAVISTIN:OAM
5JLC:His382::BAVISTIN:OAM
Tyr127, Leu130, Phe242, Leu381, Leu384, Met512

Table 5: Docking results for antifungal activity of synthesized compounds (4a-m).

Conclusion

In the present investigation, we have reported the synthesis of series of novel substituted phenyl-1,5-dihydro-2H-benzo[4,5]thiazolo[3,2-a] pyrimido[4,5-d]pyrimidine derivatives (4a-m). The desired compounds were prepared in one pot using three different components with high yields and all the synthesized compounds were screened for the antimicrobial activity. The results showed that most of the derivatives inhibited the growth with higher inhibition zones and it may due to the structural orientation and different substituents. Hence, can be used as effective antimicrobial drugs in future.

Acknowledgements

The authors are thankful to the Chairman, Department of Industrial Chemistry, Kuvempu University, Shankaraghatta for providing the laboratory facilities and IISc Bangalore for providing spectral data.

References

Citation: Venkatesh T, Bodke YD, Nagaraj K, Kumar SR (2018) One-Pot Synthesis of Novel Substituted Phenyl-1,5-dihydro-2H-benzo[4,5]thiazolo[3,2-a] pyrimido[4,5-d]pyrimidine Derivatives as Potent Antimicrobial Agents. Med Chem (Los Angeles) 8: 001-007. Doi: 10.4172/2161-0444.1000488

Copyright: © 2018 Venkatesh T, et al. 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.

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