Umesh Yadava

Pyrazolo(3,4-d)pyrimidines as inhibitor of anti-coagulation and inflammation activities of phospholipase A2: insight from molecular docking studies

Phospholipase A2 (PLA2), isolated from Daboia russelli pulchella (Russell’s viper), is enzymatically active as well as induces several pharmacological disorders including neurotoxicity, myotoxicity, cardiotoxicity, anti-coagulant, hemolytic, and platelet effects. Indomethacin reduces the effects of anti-coagulant and pro-inflammatory actions of PLA2. Pyrazolo[3,4-d]pyrimidines constitute a class of naturally occurring fused uracils that posses diverse biological activities. The in-silico docking studies of nine pyrazolo[3,4-d]pyrimidine molecules have been carried out with the X-ray crystal structure of Russell’s viper PLA2 (PDB ID: 3H1X) to predict the binding affinity, molecular recognition, and to explicate the binding modes, using AUTODOCK and GLIDE (Standard precision and Extra precision) modules, respectively. Docking results through each method make obvious that pyrazolo[3,4-d]pyrimidine molecules with trimethylene linker can bind with both anti-coagulation and enzymatic regions of PLA2.

Synthesis, QSAR and anticandidal evaluation of 1,2,3-triazoles derived from naturally bioactive scaffolds

In the present study, we used eight natural precursors (1a-h) with most of them having promising antimicrobial activities and synthesised their novel 1,2,3-triazole derivatives (3a-h). In the reaction sequences, the precursor compounds (1a-h) were converted to their respective alkyne (2a-h) followed by addition of benzyl azide freshly prepared by the reaction of benzyl bromide with sodium azide using [3 + 2] azide-alkyne cycloaddition strategy. Structural elucidation of all the triazole derivatives was done using FT-IR, (1)H, (13)C NMR, mass and elemental analysis techniques. The single crystal X-ray diffraction for 3d was also recorded. The result of in vitro anticandidal activity performed against three different strains of Candida showed that compound 3e was found superior/comparable to fluconazole (FLC) with IC50 values of 0.044 μg/mL against Candida albicans (ATCC 90028), 12.022 μg/mL against Candida glabrata (ATCC 90030), and 3.60 μg/mL against Candida tropicalis (ATCC 750). Moreover, at their IC50 values, compounds 3e and 3h showed <5% hemolysis which indicates the non-toxic behaviour of these inhibitors. Cytotoxicity assay was also performed on VERO cell line and all the derivatives were found non-toxic up to the concentration of 10.0 μg/mL. The in silico technique of 3D-QSAR was applied to establish structure activity relationship of the synthesized compounds. The results reveal the molecular fragments that play an essential role in improving the anticandidal activity.

Monocyclic β-lactam and unexpected oxazinone formation: synthesis, crystal structure, docking studies and antibacterial evaluation

Abstract Novel monocyclic β-lactam derivatives bearing aryl, phenyl and heterocyclic rings were synthesized as possible antibacterial agents. Cyclization of imines (3h, 3t) with phenylacetic acid in the presence of phosphoryl chloride and triethyl amine did not afford the expected β-lactams. Instead, highly substituted 1,3-oxazin-4-ones (4h, 4t) were isolated as the only product and confirmed by single crystal X-ray analysis of 4t. The results of antibacterial activity showed that compound 4l exhibited considerable antibacterial activity with MIC and MBC values of 62.5 µg/mL against Klebsiella pneumoniae. Cytotoxicity assay on Chinese Hamster Ovary (CHO) cell line revealed non-cytotoxic behavior of compounds 4d, 4h, 4k and 4l up to 200 μg/mL conc. Molecular docking was performed for compound 4l with penicillin binding protein-5 to identify the nature of interactions. The results of both in silico and in vitro evaluation provide the basis for compound 4l to be carried as a potential lead molecule in the drug discovery pipeline against bacterial infections.

Diketo acids and their amino acid/dipeptidic analogues as promising scaffolds for the development of bacterial methionine aminopeptidase inhibitors

Using diketoesters as the template, various derivatives were designed and the selected compounds were synthesized as bacterial methionine aminopeptidase (MetAP) inhibitors. The results of in vitro antibacterial screening revealed fifteen compounds (1a–c, 1e–h, 1j, 1l, 2a–c, 3d, 5c and 5e) as potent against different bacterial strains. By using the MTT assay on human cell line (HepG2), the viability of cell proliferation was evaluated and nine compounds (1c, 1e, 1j, 1l, 2a,b, 3d, 5c and 5e) showed no cytotoxic effect at the concentration range of 50–450 μg ml−1. In the biochemical evaluation against methionine aminopeptidase (MetAPs) from Streptococcus pneumonia (SpMetAP), Mycobacterium tuberculosis (MtMetAP), Enterococcus faecalis (EfMetAP) and human (HsMetAP), compounds displayed differential behaviour against these four enzymes. Moreover, compound 1g showed 84% inhibition of SpMetAP, while compound 3d selectively inhibited MtMetAP with 79% inhibition and little effect on HsMetAP at 100 μM concentration. At the same concentration, compound 5e exhibited 87% and 85% inhibition of EfMetAP and SpMetAP, respectively. Understanding the mode of binding through modeling at the active site provided the structural basis for the possible mode of inhibition. Together, these data will be useful for further development of diketo acid based inhibitors with improved potency and selectivity.

2,2′-Bipyridyl-acetylphenolato mixed ligand copper(II) complexes: syntheses, characterizations and catalytic activity in styrene epoxidation

Two copper(II) complexes, [Cu(bipy)(5-Br-2-hap)(ClO4)]2 (1) and [Cu(bipy)(2-hap)(ClO4)] (2) (where bipy = 2,2′-bipyridine, 5-Br-2-hap = 5-bromo-2-hydroxyacetophenone, 2-hap = 2-hydroxyacetophenone), were synthesized and characterized. The crystal structure of 1 was determined by single crystal X-ray diffraction while 2 was reported earlier. Structural characterization reveals that the presence of bromine in 5-Br-2-hap plays a structure-determining role in dimeric 1 in comparison with the mononuclear 2 where 2-hap was used. Studies of the catalytic potential toward styrene epoxidation in homogeneous system using H2O2 as oxidant reveal that 1 is more efficient than 2 with respect to epoxide selectivity.

Molecular dynamics simulation of hydrated d(CGGGTACCCG)4 as a four-way DNA Holliday junction and comparison with the crystallographic structure

Molecular dynamics (MD) simulation of decamer sequence (CGGGTACCCG)4 as a four-way Holliday junction is reported here for 15.0 ns at three different temperatures 100, 200 and 300 K, respectively, using AMBER force field. Particle mesh Ewald method has been utilised to deal long-range interaction potentials. After MD simulation, various parameters of the junction model including backbone and helical parameters have been worked out and the dynamical pathway is discussed. Structural analysis and geometrical calculations were carried out through X3DNA. The computational results obtained are compared with the previously reported crystallographic outcomes. The width and depth of the major and minor grooves of the duplex of the four arms of the DNA junction have been calculated. The variations in the C1′–C1′ distances between the two complementary strands are discussed in detail. A close observation of the results reveals that the conformation of the average simulated structure at low temperature is of ‘B’ form and the structural integrity of the DNA junction having a twofold sequence symmetry is temperature dependent. It also seems that besides the other parameters (i.e. presence of ions, solvents, etc.), temperature may be playing a key role in preserving the structural integrity of the DNA junction.

A comparison of crystallographic and DFT optimized geometries on two taxane diterpenoids and docking studies with phospholipase A2

Structure optimization of two taxane diterpenoids I and II has been carried out using GAUSSIAN03 program with B3LYP/6-31G** basis set. The structures were fully optimized without any geometric constraints. Coordinates found in crystallographic study were used as input to the GAUSSIAN. The results show that the conformations of taxoid cores are almost same as were observed from crystallography, while the conformations of the substituents are slightly different. Thus, taxoid cores are robust enough to maintain their conformations in gaseous state while the conformations of substituents may vary depending upon the reaction condition. To understand the mode of binding, the docking studies of both compounds have been carried out with Russell’s viper phospholipase A2 (vPLA2) as target using induced fit docking. The docking results show that regarding the interactions and energy for indomethacin binding with vPLA2, compound I shows the best results.

Molecular dynamics simulation of DNA duplex, analog of PPT (polypurine tract), its conformation and hydration: a theoretical study

Molecular Dynamics Simulation Study of DNA duplex is reported here in this communication. The duplex is a decamer, which consists of two non-self complementary sequences 5′(CAAAGAAAAG) and 5′(CTTTTCTTTG). This decamer is a DNA analog of the portion of the polypurine tract, which is a RNA/DNA hybrid that serves as a primer for the synthesis of the non-digestible DNA strand by human immunodeficiency virus reverse transcriptase. The result obtained is compared with the crystal structure of this decamer duplex. The calculations described here using AMBER throw light on the effect of counter ions on the binding of water molecules, within the grooves of the duplex. This study may provide important implications for understanding the functional, energetic, and specificity of the interactions of DNA/RNA with regulatory proteins, pharmaceutical agents, and other ligands.

Efficient synthesis of novel N-substituted 2-carboxy-4-quinolones via lithium bis(trimethylsilyl)amide (LiHMDS)-induced in situ cyclocondensation reaction

A different approach for the synthesis of N-substituted 2-carboxy-4-quinolones using direct reductive amination followed by LiHMDS-induced cyclocondensation has been developed. A range of analogues of the title compounds with broad substrate scope were obtained in moderate yields and good regioselectivity.

Anti-leishmanial and cytotoxic activities of amino acid-triazole hybrids: Synthesis, biological evaluation, molecular docking and in silico physico-chemical properties

According to WHO, leishmaniasis is a major tropical disease, ranking second after malaria. Significant efforts have been therefore invested into finding potent inhibitors for the treatment. In this work, eighteen novel 1,2,3-triazoles appended with l-amino acid (Phe/Pro/Trp) tail were synthesized via azide-alkyne click chemistry with moderate to good yield, and evaluated for their anti-leishmanial activity against promastigote form of Leishmania donovani (Dd8 strain). Among all, compounds 40, 43, and 53 were identified with promising anti-leishmanial activity with IC50=88.83±2.93, 96.88±12.88 and 94.45±6.51μM respectively and displayed no cytotoxicity towards macrophage cells. Moreover, compound 43 showed highest selectivity index (SI=8.05) among all the tested compounds. Supported by docking studies, the lead inhibitors (40, 43 and 53) showed interactions with key residues in the catalytic site of trypanothione reductase. The results of pharmacokinetic parameters suggest that these selected inhibitors can be carried forward for further structural optimization and pharmacological investigation.