Sridevi Chigurupati

Synthesis of alpha amylase inhibitors based on privileged indole scaffold

Twenty five derivatives of indole carbohydrazide (1-25) had been synthesized. These compounds were characterized using 1H NMR and EI-MS, and further evaluated for their α-amylase inhibitory potential. The analogs (1-25) showed varying degree of α-amylase inhibitory potential. ranging between 9.28 and 599.0µM when compared with standard acarbose having IC50 value 8.78±0.16µM. Six analogs, 25 (IC50=9.28±0.153µM), 22 (IC50=9.79±0.43µM), 4 (IC50=11.08±0.357µM), 1 (IC50=12.65±0.169µM), 8 (IC50=21.37±0.07µM) and 14 (IC50=43.21±0.14µM) showed potent α-amylase inhibition as compared to the standard acarbose (IC50=8.78±0.16µM). All other analogs displayed good to moderate inhibitory potential. Structure-activity relationship was established through the interaction of the active compounds with enzyme active site with the help of docking studies.

Biology-oriented drug synthesis (BIODS) of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl aryl ether derivatives, in vitro α-amylase inhibitory activity and in silico studies

A new library of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl aryl ether derivatives (1-23) were synthesized and characterized by EI-MS and 1H NMR, and screened for their α-amylase inhibitory activity. Out of twenty-three derivatives, two molecules 19 (IC50=0.38±0.82µM) and 23 (IC50=1.66±0.14µM), showed excellent activity whereas the remaining compounds, except 10 and 17, showed good to moderate inhibition in the range of IC50=1.77-2.98µM when compared with the standard acarbose (IC50=1.66±0.1µM). A plausible structure-activity relationship has also been presented. In addition, in silico studies was carried out in order to rationalize the binding interaction of compounds with the active site of enzyme.

Synthesis and biological evaluation of indole derivatives as α-amylase inhibitor

A series of twenty indole hydrazone analogs (1-21) were synthesized, characterized by different spectroscopic techniques such as 1H NMR and EI-MS, and screened for α-amylase inhibitory activity. All analogs showed a variable degree of α-amylase inhibition with IC50 values ranging between 1.66 and 2.65μM. Nine compounds that are 1 (2.23±0.01μM), 8 (2.44±0.12μM), 10 (1.92±0.12μM), 12 (2.49±0.17μM), 13 (1.66±0.09μM), 17 (2.25±0.1μM), 18 (1.87±0.25μM), 20 (1.83±0.63μM), and 19 (1.97±0.02μM) showed potent α-amylase inhibition when compared with the standard acarbose (1.05±0.29μM). Other analogs showed good to moderate α-amylase inhibition. The structure activity relationship is mainly focusing on difference of substituents on phenyl part. Molecular docking studies were carried out to understand the binding interaction of the most active compounds.

Synthesis and study of the α-amylase inhibitory potential of thiadiazole quinoline derivatives

α-Amylase is a target for type-2 diabetes mellitus treatment. However, small molecule inhibitors of α-amylase are currently scarce. In the course of developing small molecule α-amylase inhibitors, we designed and synthesized thiadiazole quinoline analogs (1-30), characterized by different spectroscopic techniques such as 1HNMR and EI-MS and screened for α-amylase inhibitory potential. Thirteen analogs 1, 2, 3, 4, 5, 6, 22, 23, 25, 26, 27, 28 and 30 showed outstanding α-amylase inhibitory potential with IC50 values ranges between 0.002±0.60 and 42.31±0.17μM which is many folds better than standard acarbose having IC50 value 53.02±0.12μM. Eleven analogs 7, 9, 10, 11, 12, 14, 15, 17, 18, 19 and 24 showed good to moderate inhibitory potential while seven analogs 8, 13, 16, 20, 21 and 29 were found inactive. Our study identifies novel series of potent α-amylase inhibitors for further investigation. Structure activity relationship has been established.

Identification of novel acetylcholinesterase inhibitors: Indolopyrazoline derivatives and molecular docking studies

The synthesis of novel indolopyrazoline derivatives (P1-P4 and Q1-Q4) has been characterized and evaluated as potential anti-Alzheimer agents through in vitro Acetylcholinesterase (AChE) inhibition and radical scavenging activity (antioxidant) studies. Specifically, Q3 shows AChE inhibition (IC50: 0.68±0.13μM) with strong DPPH and ABTS radical scavenging activity (IC50: 13.77±0.25μM and IC50: 12.59±0.21μM), respectively. While P3 exhibited as the second most potent compound with AChE inhibition (IC50: 0.74±0.09μM) and with DPPH and ABTS radical scavenging activity (IC50: 13.52±0.62μM and IC50: 13.13±0.85μM), respectively. Finally, molecular docking studies provided prospective evidence to identify key interactions between the active inhibitors and the AChE that furthermore led us to the identification of plausible binding mode of novel indolopyrazoline derivatives. Additionally, in-silico ADME prediction using QikProp shows that these derivatives fulfilled all the properties of CNS acting drugs. This study confirms the first time reporting of indolopyrazoline derivatives as potential anti-Alzheimer agents.

Recent discovery of non-nucleobase thymidine phosphorylase inhibitors targeting cancer

Thymidine phosphorylase (TP, EC 2.4.2.4), an enzyme involved in pyrimidine salvage pathway, is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and gliostatin. It is extremely upregulated in a variety of solid tumours. The TP amplification is associated with concomitant overexpression of many angiogenic factors such as matrix metalloproteases (MMPs), interleukins (ILs), vascular endothelial growth factor (VEGF) etc., resulting in promotion of angiogenesis and cancer metastasis. In addition, overshooting TP level protects tumour cells from apoptosis and helps cell survival. Thus, TP is identified as a prime target for developing novel anticancer therapies. Pioneering research activities investigated a large number of TP inhibitors, most of which are pyrimidine or purine analogues. Recently, an array of structurally diverse non-nucleobase derivatives was designed, synthesized and established as promising TP inhibitors. This review, following an outline on the TP structure and functions, gives an overview of the recent advancement of various non-nucleobase TP inhibitors as novel anti-cancer agents.

A Simple HPLC-UV Method for the Determination of Glutathione in PC-12 Cells

A highly sensitive and simple HPLC-UV method was developed and validated for the assay of glutathione (GSH) in PC-12 cells. Glutathione is a major intracellular antioxidant having multiple biological effects, best known for its cytoprotective effects against cell damage from reactive oxygen species and toxic reactive metabolites and regulating the cellular redox homeostasis. Due to its own sulfhydryl (SH) group, GSH readily reacts with Ellmans reagent to form a stable dimer which allows for quantitative estimation of GSH in biological systems by UV detection. The separation was achieved using a C8 column with a mobile phase consisting of phosphate buffer adjusted to pH 2.5 (mobile phase A) and acetonitrile (mobile phase B), running in a segmented gradient manner at a flow rate of 0.8 mL/min, and UV detection was performed at 280 nm. The developed HPLC-UV method was validated with respect to precision, accuracy, robustness, and linearity within a range of 1–20 μg/mL. Limit of detection (LOD) and limit of quantification (LOQ) were 0.05 and 0.1 μg/mL, respectively. Furthermore, the method shows the applicability for monitoring the oxidative stress in PC-12 cells.

New Hybrid Hydrazinyl Thiazole Substituted Chromones: As Potential α -Amylase Inhibitors and Radical (DPPH & ABTS) Scavengers

Current research is based on the identification of novel inhibitors of α-amylase enzyme. For that purpose, new hybrid molecules of hydrazinyl thiazole substituted chromones 5–27 were synthesized by multi-step reaction and fully characterized by various spectroscopic techniques such as EI-MS, HREI-MS, 1H-NMR and 13C-NMR. Stereochemistry of the iminic bond was confirmed by NOESY analysis of a representative molecule. All compounds 5–27 along with their intervening intermediates 1–4, were screened for in vitro α-amylase inhibitory, DPPH and ABTS radical scavenging activities. All compounds showed good inhibition potential in the range of IC50 = 2.186–3.405 µM as compared to standard acarbose having IC50 value of 1.9 ± 0.07 µM. It is worth mentioning that compounds were also demonstrated good DPPH (IC50 = 0.09–2.233 µM) and ABTS (IC50 = 0.584–3.738 µM) radical scavenging activities as compared to standard ascorbic acid having IC50 = 0.33 ± 0.18 µM for DPPH and IC50 = 0.53 ± 0.3 µM for ABTS radical scavenging activities. In addition to that cytotoxicity of the compounds were checked on NIH-3T3 mouse fibroblast cell line and found to be non-toxic. In silico studies were performed to rationalize the binding mode of compounds (ligands) with the active site of α-amylase enzyme.

Synthesis of azomethines derived from cinnamaldehyde and vanillin: in vitro aetylcholinesterase inhibitory, antioxidant and insilico molecular docking studies

In the present study, we report the synthesis of azomethines derived from cinnamaldehyde (C1–C3) and vanillin (V1–V3) using ethanol as a green solvent in the presence of triethyl amine. The synthesized compounds were characterized and investigated for their free radical scavenging activity and anti-Alzheimer properties by DPPH and acetylcholinesterase (AChE) inhibition assays. The anti-Alzheimer properties of the compounds were determined by molecular docking and ADME predictions. Compounds, C1 and V1 were found to be potential with IC50 values of 0.01 ± 0.09 µM and 0.31 ± 0.03 µM respectively. The antioxidant activity of C1 in terms of DPPH and ABTS was found to be 16.22 ± 0.02 µM and 17.2 ± 0.02 µM, whereas V1 showed antioxidant activities at 14.07 ± 0.02 µM and 15.06 ± 0.03 µM respectively. In silico studies based on molecular docking and ADME predictions revealed the significance of azomethine derivatives as the potent anti-Alzheimer agents.

Synthesis and in vitro study of benzofuran hydrazone derivatives as novel alpha-amylase inhibitor

The α-amylase acts as attractive target to treat type-2 diabetes mellitus. Therefore in discovering a small molecule as α-amylase inhibitor, we have synthesized benzofuran carbohydrazide analogs (1-25), characterized through different spectroscopic techniques such as 1HNMR and EI-MS. All screened analog shows good α-amylase inhibitory potentials with IC50 value ranging between 1.078±0.19 and 2.926±0.05µM when compared with acarbose having IC50=0.62±0.22µM. Only nine analogs among the series such as analogs 3, 5, 7, 8, 10, 12, 21, 23 and 24 exhibit good inhibitory potential with IC50 values 1.644±0.128, 1.078±0.19, 1.245±0.25, 1.843±0.19, 1.350±0.24, 1.629±0.015, 1.353±0.232, 1.359±0.119 and 1.488±0.07µM when compare with standard drug acarbose. All other analogs showed good to moderate α-amylase inhibitory potentials. The SAR study was conducted on the basis of substituent difference at the phenyl ring. The binding interaction between analogs and active site of enzyme was confirmed by docking studies.