4-Thiazolidinone coumarin derivatives as two-component NS2B/NS3 DENV flavivirus serine protease inhibitors: synthesis, molecular docking, biological evaluation and structure–activity relationship studies
© The Author(s) 2018
Received: 26 February 2018
Accepted: 12 May 2018
Published: 12 June 2018
Coumarins are biologically active members of the benzopyrone family. Their derivatives are reported to display various biological activities such as as anti-bacterial [12, 13], anti-fungal [14–16], anti-coagulant , anti-dengue , anti-tuberculosis , anti-viral , anti-tumor [21, 22], anti-HIV  and anti-cytotoxicity . Impressed by the strong biologically active profile of coumarin derivatives and as a part of our interest in the synthesis and screening of potentially bioactive compounds , we herein, report the synthesis of some novel 4-thiazolidinone coumarin hybrids (SKYa–SKYg) to be evaluated for their in vitro anti-bacterial, anti-tubercular activities, and as nonsubstrate based dengue virus NS2B/NS3 serine protease inhibitors via molecular docking approach. We targeted to study the structure–activity-relationship by altering the position of the substituents within the coumarin nucleus, as it is important to recognize the structural features in the coumarin nucleus for the design and development of new coumarin derivatives with remarkable biological activities.
Results and discussion
Synthesis of 4-thiazolidinone coumarin derivatives by application of Pearson’s HSAB principle
In-vitro anti-bacterial activity
Anti-bacterial and anti-tuberculosis activities (MIC, μg/mL) of coumarin hybrids (SKYa–SKYg)
In-vitro anti-tuberculosis activity
To complete the multi-target biological profile of the test compounds (SKYa–SKYg), the in vitro anti-TB inhibitory activity against M. tuberculosis, H37Rv strain ATCC 25618 was measured with reference to the control drug isoniazid. All the test compounds except SKYg exhibited anti-TB activity with the highest chosen concentration level of 50 μg/mL. Results obtained for SKYb, SKYd, SKYe and SKYf indicated that the introduction of halogen and methoxy group could enhance the anti-TB activity. It was also apparent from the results that the introduction of hydroxyl could also exert considerable anti-TB activity as shown by compounds SKYc with MIC values of 132, 151 and 158 μg/mL, respectively. Compound SKYg showed no significant inhibitory activity, indicating that all compounds are clearly selective inhibitors and that the presence of nitro group had no inhibitory effects on the tubercle cells even at the highest concentration range of 50 μg/mL. Compared to the standard, these active compounds fared moderately (Fig. 5). Concerning anti-TB activity, compounds possessing MIC values of 1.5 μg/mL are considered promising . However, these compounds might not be drugs per se if they are toxic, insoluble or pharma kinetically limited. Noticeably, the structural differences of the compounds could provide ideas for the designing of new anti-microbial agents. Therefore, the structural skeleton of compounds SKYb, SKYc and SKYd could also provide a useful template for the development of new anti-TB drugs (Table 1).
Structure–activity-relationship (SAR) analysis
Substituents play a very important role in the bio-activity of any molecule. The position and site of attachment of the group (for example; thiazole ring, halogen, methyl, methoxy, hydroxyl, nitro and amino substituents) and its electronic nature contributes profoundly to its bioactive profile . The SAR reveals that physiochemical properties such as lipophilicity or hydrophobicity and electronegativity of any substituent effectively controls its bio-activeness towards any pathogen. The more hydrophobic the substituent, the more effective are its antibacterial and anti-tubercular properties. Bio-activity of 4-thiazolidinone-coumarins seems to increase 4 to 8 folds more in the presence of halogen or hydroxyl groups (good hydrophobic), when compared to the standards streptomycin, kanamycin and vancomycin. In the presence of OCH3 group (moderate hydrophobic), the bio-activeness was reported as between good and moderate and NO2 group (hydrophilic), was found to exhibit relatively lower bio-activity. A quite satisfactory explanation behind this, is the high electronegativity and high effective nuclear charge of the halogens which make them quite reactive and thus they tend to increase the lipophilicity or hydrophobicity of the molecules, making them bigger, more polarized and accordingly increasing the London dispersion forces, which are responsible for the interaction of the lipophilic substance to themselves or with others. Alcoholic hydroxyl groups (-OH), are quite polar and hence hydrophilic (water loving) in nature. But, is should be noted that their carbon chain portion is non-polar which makes them hydrophobic, overall more nonpolar and therefore less soluble in the polar water as the carbon chain grows. The methoxy group (OCH3) on the other hand has little influence on the molecular hydrophobicity and its bio-activities are between good and moderate. Opposite to these the nitro functional groups (NO2) are hydrophilic which form strong hydrogen bonds with water molecules, despite of their high polarities arising due to large dipole moments. As a result, these compounds are hydroneutral, with hydrophilicity between hydrophilic and hydrophobic . The overall results showed, that the bio-activities of the tested compounds increased several times with the halogen or hydroxyl groups in the coumarin skeleton (SKYb, SKYc). Whereas the activity was in between good to moderate in the presence of OCH3 (SKYd, SKYe, SKYf) and NO2 group (SKYg). Therefore, it could be concluded that by replacing or changing the groups in the coumarin pharmacophore could result in better structural modifications of the molecule making them display even more better bio-activities.
The molecular docking methodology can provide a greater understanding of the ligand–protein interactions. With this motive, all the synthesized compounds were docked into the active site of enzyme. Docking against the dengue virus NS2B/NS3 protease helps immensely in the prediction of their interaction ability. For results comparison, 4-hydroxypanduratin (DS − 3.379), panduratin (DS − 3.189) and ethyl 3-(4-(hydroxymethyl)-2-methoxy-5-nitrophenoxy)propanoate (DS − 3.381) were docked as positive controls. The 3D crystallographic structure of DENV NS2B/NS3 protease was obtained from PDB (PBD ID: 2FOM), at a resolution of 1.50 Å. The aim is to target the hydrophobic pockets of dengue virus NS2B/NS3 protease, and to screen all compounds that could help in the inhibition of DENV infection. The results thus could offer useful information in the development of drug and would further help in computer-aided drug designing, against the DENV infection. Dengue virus possess of four antigenically related serotypes, such as dengue S-1, S-2, S-3 and S-4 [7, 31] and interestingly any of the inhibitor could act against these serotypes, in the binding pocket of NS2B/NS3 protease . Heavy number of envelope proteins surrounds the mature dengue virus at its surface, hence initiating the points for the systematic search of cavities to help discover those compounds that could interfere in the E protein rearrangements, which results in fusion process . Like other flavivirus, dengue virus has also been specified as a significant drug target. As its catalytic triad is already known to be quite important in viral replication, therefore any disruption in it could block the replication of the DENV .
Compounds (SKYa–SKYg), docking score, interacting residues and close contact residues
Close contact residues
HIS51, ASP75, TYR150, GLY151, ASN152, GLY153, SER135, PRO132, SER131, PHE130, LEU128
HIS51 (H bond) and (two π-cation)
ASP75, VAL154, GLY153, ASN152, GLY151, TYR150, HIS51, LEU128, PHE130, SER131, PRO132, SER135
GLY153 (H bond), PHE130 (H bond), HIS51 (π–π stacking and π-cation)
HIS51, GLY153, GLY151, TYR150, LEU128, PHE130, SER131, PRO132, SER135
PHE130 (H bond), HIS51 (π–π stacking and π-cation)
HIS51, GLY153, GLY151, TYR150, LEU128, PHE130, SER131, PRO132, SER135
GLY153 (H Bond), PHE130 (H Bond), HIS51 (π–π stacking and π-cation)
GLY153, GLY151, TYR150, LEU128, PHE130, SER131, PRO132, SER135
GLY153 (H bond), PHE130 (H bond), HIS51 (π–π stacking and π-cation)
HIS51, ASP75, GLY153, ASN152, GLY151, TYR150, LEU, PHE130, SER131, PRO132, THR134, SER135
GLY151 and LEU128 (H bond)
HIS51, ASP75, GLY153, ASN152, GLY151, TYR150, SER135, PRO132, SER131, PHE130, ASP129, LEU128
Materials and methods
Solvents and reagents of analytical grade were purchased from Sigma-Aldrich, ACROS Organics and Merck and used as it is unless otherwise stated, the normal workup from organic solvent involved drying over Na2SO4, MgSO4 and rotary evaporation. TLC was performed on aluminium-backed Merck Silica Gel 60 F-254 sheets using suitable solvent systems with spots being visualized by a UV Lamp (254 or 365 nm). Deuterated solvents were used as received. Melting points were obtained in open capillary tubes using a Stuart Scientific (SMP-1) instrument and were uncorrected. The FTIR spectra was recorded using Perkin Elmer FTIR-ATR spectrometer Frontier as KBr pellets at the wavelength of 4000–650/cm. 1D and 2D NMR spectra were recorded on a Bruker Avance 500 FT-NMR instrument at 500 MHz for 1H and 2D NMR experiments (COSY, HMQC and HMBC) and at 125 MHz for 13C NMR, DEPT 90 and DEPT 135 experiments, using TMS as internal standard and DMSO-d6 as solvent. Bruker Topspin software v 3.0 was used to process the NMR raw data. Chemical shifts were expressed in parts per million on δ scale and the coupling constants were given in Hertz (Hz). Mass spectra were conducted on an Agilent Technologies 6224 TOF LC–MS spectrometer. The measurements were carried out in positive mode. Elemental analyses were accomplished on a Perkin Elmer 2400 series Elemental CHN analyzer and were within ± 0.3% of the theoretical values. Automated docking studies for dengue were carried out using the Maestro™ software package (v. 12.1, Schrödinger, LLC, New York, NY, 2011) program.
General procedure for the synthesis of 3-acetylcoumarins (3a–1g) and coumarin thiosemicarbazones (5a–5g)
To a cooled mixture of salicylaldehyde derivatives (1a–1g) (0.20 mol) and ethyl acetoacetate 2 (0.25 mol) a catalytic amount of piperidine was added with continuous stirring. The reaction mixture was rested for 12 h, resulting in the formation of a yellow solid which was washed with cold ether and recrystallized by ethanol/CHCl3 (1:3, v/v) mixtures, to afford pure 3-acetylcoumarins (3a–3g) as fine yellow needles in good yields. Thiosemicarbazide (4) (2.8 mmol) was added to the methanolic solution of the series of corresponding acetyl coumarin (3a–3g) (2.8 mmol), along with a few drops of glacial acetic acid. After 4 h of refluxing, the precipitate was filtered and washed with cold water. Recrystallization from ethanol/ethyl acetate (2:1, v/v) afforded good yields of coumarin thiosemicarbazones (5a–5g) (Scheme 1) .
General procedure for the synthesis of 4-thiazolidinone coumarin hybrids (SKYa–SKYg)
A mixture of various corresponding coumarin thiosemicarbazone (5a–5g) (0.01 mol), anhydrous sodium acetate (6) (0.01 mol) and monochloroacetic acid (7) (0.01 mol) in absolute ethanol (20 mL) was heated under reflux for 5 h with continuous stirring. Initially a clear solution was formed which on slow evaporation of excess solvent gave whitish solid. Work-up and recrystallization from EtOH/water afforded the target compounds (SKYa–SKYg) as white colour solids in good yields (Scheme 2) .
(Z)-2-((E)-(1-(2-Oxo-2H-chromen-3-yl)ethylidene)hydrazono)thiazolidin-4-one ( SKYa )
White solid, (1.90 g, 63.1%), mp 256–258 °C. IR KBr (νmax/cm−1): 3156.15 (N–H), 1723.06 (C=O lactone), 1626.05 (C=O keto), 1609.07 (C=N); 1H NMR (δ/ppm, 500 MHz, DMSO-d 6 ): 12.24 (1H, br s, N–H), 8.19 (1H, s, H-4), 7.87 (1H, dd, J = 7.5, 1.5 Hz, H-5), 7.67 (1H, td, J = 8.5, 7.0, 1.5 Hz, H-7), 7.45 (1H, d, J = 8.0 Hz, H-8), 7.40 (1H, td, J = 7.5, 0.5 Hz, H-6), 3.91 (2H, s, H-14), 2.32 (3H, s, CH3); 13C NMR (δ/ppm, 125 MHz, DMSO-d 6 ): 173.90 (C-11), 165.16 (C-13), 159.43 (C-2), 159.00 (C-9), 153.47 (C-8a), 141.53 (C-4), 132.58 (C-7), 129.28 (C-5), 126.48 (C-3), 124.77 (C-6), 118.67 (C-4a), 115.99 (C-8), 32.85 (C-14), 16.93 (CH3). Anal. Calcd. For C14H11O3N3S (301.32/gmol): C, 55.80; H, 3.68; N, 13.95%. Found: C, 55.86; H, 3.64; N, 13.90%. MS (+ESI) (m/z): 302.0578 (301.0521).
(Z)-2-((E)-(1-(6-Bromo-2H-chromen-3-yl)ethylidene)hydrazono)thiazolidin-4-one ( SKYb )
White solid, (2.57 g, 67.6%), mp 249–251 °C. IR KBr (νmax/cm−1): 3152.26 (N–H), 1733.03 (C=O lactone), 1690.11 (C=O keto), 1622.09 (C=N); 1H NMR (δ/ppm, 500 MHz, DMSO-d 6 ): 12.23 (1H, br s, N–H), 8.16 (2H, s, H-4 & H-5), 7.80 (1H, dd, J = 9.0, 205 Hz, H-7), 7.42 (1H, d, J = 8.5 Hz, H-8), 3.90 (2H, s, H-14), 2.30 (3H, s, CH3); 13C NMR (δ/ppm, 125 MHz, DMSO-d 6 ): 174.17 (C-11), 165.88 (C-13), 158.93 (C-2), 158.54 (C-8a), 152.52 (C-9), 140.14 (C-4), 134.75 (C-7), 131.22 (C-5), 127.55 (C-3), 120.63 (C-6), 118.25 (C-8), 116.25 (C-4a), 32.95 (C-14), 16.87 (CH3). Anal. Calcd. For C14H10O3N3SBr (380.22/gmol): C, 44.22; H, 2.65; N, 11.05%. Found: C, 44.18; H, 2.69; N, 11.00%. MS (+ESI) (m/z): 381.0902 (378.9626).
(Z)-2-((E)-(1-(7-Hydroxy-2H-chromen-3-yl)ethylidene)hydrazono)thiazolidin-4-one ( SKYc )
White solid, (2.48 g, 78.2%), mp 261–263 °C. IR KBr (νmax/cm−1): 3450.20 (O–H), 3096.74 (N–H), 1723.63 (C=O lactone), 1693.97 (C = O keto), 1625.15 (C=N); 1H NMR (δ/ppm, 500 MHz, DMSO-d 6 ): 11.71 (1H, br s, N–H), 8.10 (1H, s, H-4), 7.69 (1H, d, J = 9.5 Hz, H-5), 6.84 (1H, dd, J = 8.5, 2.5 Hz, H-6), 6.76 (1H, d, J = 2.5 Hz, H-8), 3.88 (2H, s, H-14), 3.35 (1H, s, O–H), 2.30 (3H, s, CH3); 13C NMR (δ/ppm, 125 MHz, DMSO-d 6 ): 173.91 (C-11), 162.05 (C-13), 159.40 (C-2), 157.67 (C-8a), 155.65 (C-9), 142.11 (C-4), 130.80 (C-7), 129.26 (C-5), 121.64 (C-4a), 111.17 (C-3), 101.79 (C-6), 66.32 (C-8), 32.80 (C-14), 23.12 (CH3). Anal. Calcd. For C14H11O4N3S (317.32/gmol): C, 52.99; H, 3.49; N, 13.24%. Found: C, 53.03; H, 3.53; N, 13.28%. MS (+ESI) (m/z): 318.2988.
(Z)-2-((E)-(1-(6-Methoxy-2H-chromen-3-yl)ethylidene)hydrazono)thizolidin-4-one ( SKYd )
White solid, (2.54 g, 76.7%), mp 248–250 °C. IR KBr (νmax/cm−1): 3143.76 (N–H), 1721.04 (C=O lactone), 1702.14 (C=O keto), 1621.37 (C=N); 1H NMR (δ/ppm, 500 MHz, DMSO-d 6 ): 12.10 (1H, br s, N–H), 8.13 (2H, s, H-4), 7.44 (1H, d, J = 3.0 Hz, H-5), 7.39 (1H, d, J = 9.0 Hz, H-7), 7.42 (1H, d, J = 9.0, 3.0 Hz, H-8), 3.88 (2H, s, H-14), 3.82 (3H, s, OCH3), 2.30 (3H, s, CH3); 13C NMR (δ/ppm, 125 MHz, DMSO-d 6 ): 173.93 (C-11), 164.75 (C-13), 163.08 (C-2), 159.50 (C-8a), 159.26 (C-9), 155.54 (C-4), 141.81 (C-7), 130.45 (C-5), 122.68 (C-3), 112.89 (C-6), 112.24 (C-4a), 100.32 (C-8), 56.03 (OCH3), 32.83 (C-14), 16.92 (CH3). Anal. Calcd. For C15H13O4N3S (331.35/gmol): C, 54.37; H, 3.95; N, 12.68%. Found: C, 54.41; H, 3.91; N, 12.64%. MS (+ESI) (m/z): 332.0697 (331.0626).
(Z)-2-((E)-(1-(7-Methoxy-2H-chromen-3-yl)ethylidene)hydrazono)thiazolidin-4-one ( SKYe )
White solid, (2.62 g, 79.1%), mp 259–261 °C. IR KBr (νmax/cm−1): 3120.09 (N–H), 1726.12 (C=O lactone), 1715.02 (C=O keto), 1612.77 (C=N); 1H NMR (δ/ppm, 500 MHz, DMSO-d 6 ): 12.00 (1H, br s, N–H), 8.12 (2H, s, H-4), 7.79 (1H, d, J = 9.0 Hz, H-5), 7.04 (1H, d, J = 2.0 Hz, H-8), 6.99 (1H, dd, J = 9.0, 2.5 Hz, H-6), 3.88 (3H, s, OCH3), 3.87 (2H, s, H-14), 2.31 (3H, s, CH3); 13C NMR (δ/ppm, 125 MHz, DMSO-d 6 ): 173.93 (C-11), 164.75 (C-13), 163.08 (C-2), 159.50 (C-8a), 159.26 (C-9), 155.54 (C-4), 141.81 (C-7), 130.45 (C-5), 122.68 (C-3), 112.89 (C-6), 112.24 (C-4a), 100.32 (C-8), 56.03 (OCH3), 32.83 (C-14), 16.92 (CH3). Anal. Calcd. For C15H13O4N3S (331.35/gmol): C, 54.37; H, 3.95; N, 12.68%. Found: C, 54.33; H, 4.0; N, 12.64%. MS (+ESI) (m/z): 332.0705 (331.0626).
(Z)-2-((E)-(1-(8-Methoxy-2H-chromen-3-yl)ethylidene)hydrazono)thiazolidin-4-one (SKYf )
White solid, (2.70 g, 81.6%), mp 269–271 °C. IR KBr (νmax/cm−1): 3233.60 (N–H), 1731.48 (C=O lactone), 1684.00 (C=O keto), 1608.48 (C=N); 1H NMR (δ/ppm, 500 MHz, DMSO-d 6 ): 12.01 (1H, br s, N–H), 8.16 (2H, s, H-4), 7.41 (1H, dd, J = 7.5, 2.0 Hz, H-5), 7.31–7.37 (2H, m, H-6 & H-7), 3.94 (3H, s, OCH3), 3.89 (2H, s, H-14), 2.32 (3H, s, CH3); 13C NMR (δ/ppm, 125 MHz, DMSO-d 6 ): 173.88 (C-11), 165.19 (C-13), 159.37 (C-2), 158.71 (C-8a), 146.29 (C-9), 142.84 (C-4), 141.72 (C-7), 26.62 (C-4a), 124.70 (C-5), 120.39 (C-6), 119.25 (C-3), 114.80 (C-8), 56.15 (OCH3), 32.85 (C-14), 16.92 (CH3). Anal. Calcd. For C15H13O4N3S (331.35): C, 54.37; H, 3.95; N, 12.68%. Found: C, 54.33; H, 4.0; N, 12.64%. MS (+ESI) (m/z): 332.0696 (331.0626).
(Z)-2-((E)-(1-(6-Nitro-2H-chromen-3-yl)ethylidene)hydrazono)thiazolidin-4-one( SKYg )
White solid, (2.73 g, 78.9%), mp 235–237 °C. IR KBr (νmax/cm−1): 3134.72 (N–H), 1732.12 (C=O lactone), 1683.40 (C=O keto), 1622.59 (C=N); 1H NMR (δ/ppm, 500 MHz, DMSO-d 6 ): 12.21 (1H, br s, N–H), 8.11 (1H, s, H-4), 7.39 (1H, d, J = 2.5 Hz, H-5), 7.79 (1H, dd, J = 8.5, 2.0 Hz, H-7), 7.41 (1H, d, J = 8.0 Hz, H-8), 3.92 (2H, s, H-14), 2.32 (3H, s, CH3); 13C NMR (δ/ppm, 125 MHz, DMSO-d 6 ): 173.12 (C-11), 163.00 (C-13), 157.23 (C-2), 158.45 (C-8a), 151.52 (C-9), 140.14 (C-4), 134.67 (C-7), 131.20 (C-5), 126.55 (C-3), 120.23 (C-6), 119.27 (C-8), 117.78 (C-4a), 35.89 (C-14), 19.85 (CH3). Anal. Calcd. For C14H10O5N4S (346.32): C, 48.55; H, 2.91; N, 16.18%. Found: C, 48.85; H, 2.87; N, 16.22%. MS (+ESI) (m/z): 347.0403 (346.0371).
In-vitro evaluation of anti-bacterial activity
The anti-bacterial bioactivity profile of the synthesized derivatives was performed by broth microdilution method using tetrazolium microplate assay (TEMA) . All the hybrid molecules were screened in vitro against two Gram-positive bacteria (S. pneumoniae and S. aureus) and three Gram-negative bacteria (E. coli, E. aerogenes and S. typhi) and the MIC was reported in μg/mL. The bacterial cultures were freshly grown, emulsified in Muller Hinton broth (MHB) and incubated until the log phase growth was achieved. Its turbidity was then matched to McFarland standard no. 0.5 to achieve the inoculum concentration of 1.5 × 108 CFU/mL. The test was performed in triplicates making serial twofold concentrations ranging between 3.91 and 250 μg/mL. Coloring reagent 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) was used to identify the results. The MIC was calculated as the lowest concentration of compounds that prevented the colour change from yellow to purple. DMSO was used as a negative control in this assay while streptomycin, kanamycin and vancomycin were used as positive controls.
In-vitro evaluation of anti-tuberculosis activity
A well-characterized H37Rv ATCC 25618 virulent strain of M. tuberculosis was used to complete the anti-tuberculosis activity of the synthesized compounds by colorimetric microdilution assay, using tetrazolium salt as a colouring reagent, following our previously reported broth micro dilution method and by using isoniazid as a positive control and DMSO as a negative control . The mycobacterial inoculum was prepared by a 5 day old freshly grown culture in Middlebrook 7H9 broth, supplemented with 0.2% glycerol, 0.05% Tween 80 and 10% albumin, dextrose and catalase (ADC) supplement. The inoculum turbidity was adjusted to McFarland standard no. 1 to achieve the concentration of 3 × 108 CFU/mL. Middlebrook 7H9 broth supplemented with oleic, albumin, dextrose and catalase (OADC) was then used to further dilute it, in a ratio of 1:20. 2-Fold serial dilution was made in 96-well microtiter plate in the range of 0.195–50 μg/mL. Each microtiter plate was sealed and incubated for 5 days at 37 °C in 8% CO2, followed by the addition of 50 μL of tetrazolium-tween 80 mixtures (1.5 mL of 1 mg/mL MTT in absolute ethanol and 1.5 mL of 10% Tween-80). After tetrazolium addition, the plates were incubated again for the next 24 h at 37 °C. Next day the bacterial viability was registered for each well based on the color change of yellow MTT to purple formazan and the MIC was defined as the lowest concentration of compound that totally inhibited bacterial growth (no color change). The assays were performed in triplicates.
Protocol of molecular modelling and docking
Molecular docking study for all compounds was performed to predict the anti-dengue activity on structural basis of coumarin derivatives. Binding interactions ability and orientations direction of the most active inhibitors to the potent site of the enzyme pocket were used to predict their binding modes, binding affinities, and orientations at the active site of the enzyme, A 3D structure of the enzyme was derived from Protein Data Bank website with code (PDB ID: 2FOM). All water molecules and hetero groups were removed from the receptor crystal structure beyond the radius of 5 Å of the reference ligands and protein structure was refined by employs OPLS-2005 force field calculations and minimization using the Protein Preparation Wizard™ software. The Receptor Grid Generation™ applied to generate active sites residues and used it to dock the optimized ligands into the respective receptor. The structures of all compounds were drawn using ChemDraw Ultra from the ChemOffice software package. Then, it was imported into ligands preparation and optimization by using LigPrep™ application were performed with OPLS-2005 force field calculation also to generate the lowest energy state of each ligand. Docking binding stimulation was finally carried out for five poses per ligand and the pose with highest score was displayed and recorded for each ligand [35–37].
In the present work, conjugated thiazolidinone molecules (SKYa–SKYg) derived from coumarins linked by hydrazine moiety have been successfully synthesized by application of Pearson’s HSAB principle. Anti-bacterial and anti-TB activity testing of all the molecules revealed that most of the hybrids displayed activity against the bacterial and tubercle cells. In particular, compound SKYb exhibited the highest anti-bacterial profile against all the pathogens. Significantly, the analogue SKYc, SKYd and SKYe also displayed potent activities (99–378 μg/mL). Compound SKYa displayed enhanced anti-TB activity. Results also showed considerable anti-TB activity by compound SKYb (MIC 132 μg/mL). Importantly, anti-dengue results concluded that conjugate SKYf exhibited the most potent activity (DS − 4.014) followed by compound SKYd (DS − 3.964), compound SKYc (DS − 3.905) and compound SKYe (DS − 3.889). Compounds SKYg (DS − 2.992), SKYb (DS − 2.960) and SKYa (DS − 2.754) also displayed very good results when all were compared to the standards 4-hydroxypanduratin (DS − 3.379), panduratin (DS − 3.189) and ethyl 3-(4-(hydroxymethyl)-2-methoxy-5-nitrophenoxy)propanoate (DS –3.381). Docking results proved that the hydrophobic interaction between compounds and protein, inside the active pocket is the most important interaction to increase the activity of compounds against the dengue virus. This study presents novel 4-thiazolidinone-coumarin-hydrazine hybrids as potential lead molecules for further structural optimization as anti-bacterial, anti-TB and anti-dengue agents.
All authors read and approved the final manuscript.
Samina Khan Yusufzai (SKY) thanks the Institute of Postgraduate Studies (IPS), Universiti Sains Malaysia (USM) for the Graduate Assistance fellowship support. SKY expresses the gratitude to the School of Biological Sciences, USM and Faculty of Science and Natural Resources, Universiti Malaysia Sabah (UMS) for providing facilities for biological studies.
The authors declare that they have no competing interests.
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Ethics approval and consent to participate
Hasnah Osman would like to thank the Malaysian Government and USM for the Research University Grant—FRGS 203/PKIMIA/6711462. Mohammad Shaheen Khan thanks the Malaysian Government and UMS for providing Research Grant SBK0329-2017.
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