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Synthesis, HIV-1 RT inhibitory, antibacterial, antifungal and binding mode studies of some novel N-substituted 5-benzylidine-2,4-thiazolidinediones.

Bahare RS, Ganguly S, Choowongkomon K, Seetaha S - Daru (2015)

Bottom Line: Conformations of the structures were assigned on the basis of results of different spectral data.Some of the compounds have shown significant activity.Molecular docking studies showed very good interaction.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India. radhe118@gmail.com.

ABSTRACT

Background: Structural modifications of thiazolidinediones at 3rd and 5th position have exhibited significant biological activities. In view of the facts, and based on in silico studies carried out on thiazolidine-2,4-diones as HIV-1- RT inhibitors, a novel series of 2,4-thiazolidinedione analogs have been designed and synthesized.

Methods: Title compounds were prepared by the reported method. Conformations of the structures were assigned on the basis of results of different spectral data. The assay of HIV-1 RT was done as reported by Silprasit et al. Antimicrobial activity was determined by two fold serial dilution method. Docking study was performed for the highest active compounds by using Glide 5.0.

Results: The newly synthesized compounds were evaluated for their HIV-1 RT inhibitory activity. Among the synthesized compounds, compound 24 showed significant HIV-1 RT inhibitory activity with 73% of inhibition with an IC50 value of 1.31 μM. Compound 10 showed highest activity against all the bacterial strains.A molecular modeling study was carried out in order to investigate the possible interactions of the highest active compounds 24, 10 and 4 with the non nucleoside inhibitory binding pocket(NNIBP) of RT, active site of GlcN-6-P synthase and cytochrome P450 14-α-sterol demethylase from Candida albicans (Candida P450DM) as the target receptors respectively using the Extra Precision (XP) mode of Glide software.

Conclusion: A series of novel substituted 2-(5-benzylidene-2,4-dioxothiazolidin-3-yl)-N-(phenyl)propanamides (4-31) have been synthesized and evaluated for their HIV-1 RT inhibitory activity, antibacterial and antifungal activities. Some of the compounds have shown significant activity. Molecular docking studies showed very good interaction.

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2D sketch views. Binding mode of a) Ref. ligand (TNK-651) b) efavirenz c) compound 24 into the NNIBP of 1RT2 d) Glucosamine-6-Phosphate (2VF5) e) Ref ligand fluconazole (chimeric 1EA1) and compounds f) 10 in the active site of 2VF5 g) 4 in the active site of chimeric 1EA1.
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Fig2: 2D sketch views. Binding mode of a) Ref. ligand (TNK-651) b) efavirenz c) compound 24 into the NNIBP of 1RT2 d) Glucosamine-6-Phosphate (2VF5) e) Ref ligand fluconazole (chimeric 1EA1) and compounds f) 10 in the active site of 2VF5 g) 4 in the active site of chimeric 1EA1.

Mentions: To validate the Glide software, firstly the interaction between TNK651 and HIV-1 RT was modeled. Superimposition of the experimental bound (co-crystallized) conformation of TNK651 [41] and that predicted by Glide are shown in Figure 2a. Glide successfully reproduced the experimental binding conformations of TNK 651 in the NNRTI-binding pocket of HIV-1 RT with an acceptable root-mean-square deviation (RMSD) of 2.4 Å. Visual inspection was then performed on the resulting docking solutions of the compound 24 to analyze the binding mode and key protein ligand interactions and was compared with that of the experimentally determined binding mode and interactions of the bound ligand TNK-651 and the standard efavirenz. The key interactions were mainly hydrogen bonding interactions with Lys103 and Lys101 respectively. The carbonyl oxygen at position 4 in the thiazolidinedione moiety forms a strong H-bond interaction with the NH terminal group of Lys103.Another strong H-bond interaction of the hydroxyl group at the ortho position of the first phenyl ring with one of carbonyl oxygen atoms of Lys101 was observed. The phenyl ring in the 2, 3, 4-trihydroxybenzaldehyde moiety along with the thiazolidinedione moiety was oriented in the bigger hydrophobic pocket formed by Phe227, Pro225 Leu234 Tyr181, Tyr188, Leu100 and Val179 while the CH2CH2CONH linker showed favorable interaction with the amino acid residues Tyr318, Pro236 and Val106. Docking score of the compound 24 (Glide XP score-11.30) was lower than the bound ligand TNK-651(Glide XP score-13.29) but comparable to that of standard efavirenz (Glide XP score-11.33) .Possible interactions for the reference ligand TNK-651, efavirenz and compound 24 have been shown in Figure 2a,b and c respectively.Figure 2


Synthesis, HIV-1 RT inhibitory, antibacterial, antifungal and binding mode studies of some novel N-substituted 5-benzylidine-2,4-thiazolidinediones.

Bahare RS, Ganguly S, Choowongkomon K, Seetaha S - Daru (2015)

2D sketch views. Binding mode of a) Ref. ligand (TNK-651) b) efavirenz c) compound 24 into the NNIBP of 1RT2 d) Glucosamine-6-Phosphate (2VF5) e) Ref ligand fluconazole (chimeric 1EA1) and compounds f) 10 in the active site of 2VF5 g) 4 in the active site of chimeric 1EA1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4308940&req=5

Fig2: 2D sketch views. Binding mode of a) Ref. ligand (TNK-651) b) efavirenz c) compound 24 into the NNIBP of 1RT2 d) Glucosamine-6-Phosphate (2VF5) e) Ref ligand fluconazole (chimeric 1EA1) and compounds f) 10 in the active site of 2VF5 g) 4 in the active site of chimeric 1EA1.
Mentions: To validate the Glide software, firstly the interaction between TNK651 and HIV-1 RT was modeled. Superimposition of the experimental bound (co-crystallized) conformation of TNK651 [41] and that predicted by Glide are shown in Figure 2a. Glide successfully reproduced the experimental binding conformations of TNK 651 in the NNRTI-binding pocket of HIV-1 RT with an acceptable root-mean-square deviation (RMSD) of 2.4 Å. Visual inspection was then performed on the resulting docking solutions of the compound 24 to analyze the binding mode and key protein ligand interactions and was compared with that of the experimentally determined binding mode and interactions of the bound ligand TNK-651 and the standard efavirenz. The key interactions were mainly hydrogen bonding interactions with Lys103 and Lys101 respectively. The carbonyl oxygen at position 4 in the thiazolidinedione moiety forms a strong H-bond interaction with the NH terminal group of Lys103.Another strong H-bond interaction of the hydroxyl group at the ortho position of the first phenyl ring with one of carbonyl oxygen atoms of Lys101 was observed. The phenyl ring in the 2, 3, 4-trihydroxybenzaldehyde moiety along with the thiazolidinedione moiety was oriented in the bigger hydrophobic pocket formed by Phe227, Pro225 Leu234 Tyr181, Tyr188, Leu100 and Val179 while the CH2CH2CONH linker showed favorable interaction with the amino acid residues Tyr318, Pro236 and Val106. Docking score of the compound 24 (Glide XP score-11.30) was lower than the bound ligand TNK-651(Glide XP score-13.29) but comparable to that of standard efavirenz (Glide XP score-11.33) .Possible interactions for the reference ligand TNK-651, efavirenz and compound 24 have been shown in Figure 2a,b and c respectively.Figure 2

Bottom Line: Conformations of the structures were assigned on the basis of results of different spectral data.Some of the compounds have shown significant activity.Molecular docking studies showed very good interaction.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India. radhe118@gmail.com.

ABSTRACT

Background: Structural modifications of thiazolidinediones at 3rd and 5th position have exhibited significant biological activities. In view of the facts, and based on in silico studies carried out on thiazolidine-2,4-diones as HIV-1- RT inhibitors, a novel series of 2,4-thiazolidinedione analogs have been designed and synthesized.

Methods: Title compounds were prepared by the reported method. Conformations of the structures were assigned on the basis of results of different spectral data. The assay of HIV-1 RT was done as reported by Silprasit et al. Antimicrobial activity was determined by two fold serial dilution method. Docking study was performed for the highest active compounds by using Glide 5.0.

Results: The newly synthesized compounds were evaluated for their HIV-1 RT inhibitory activity. Among the synthesized compounds, compound 24 showed significant HIV-1 RT inhibitory activity with 73% of inhibition with an IC50 value of 1.31 μM. Compound 10 showed highest activity against all the bacterial strains.A molecular modeling study was carried out in order to investigate the possible interactions of the highest active compounds 24, 10 and 4 with the non nucleoside inhibitory binding pocket(NNIBP) of RT, active site of GlcN-6-P synthase and cytochrome P450 14-α-sterol demethylase from Candida albicans (Candida P450DM) as the target receptors respectively using the Extra Precision (XP) mode of Glide software.

Conclusion: A series of novel substituted 2-(5-benzylidene-2,4-dioxothiazolidin-3-yl)-N-(phenyl)propanamides (4-31) have been synthesized and evaluated for their HIV-1 RT inhibitory activity, antibacterial and antifungal activities. Some of the compounds have shown significant activity. Molecular docking studies showed very good interaction.

Show MeSH