Design, Synthesis and Pharmacological Evaluation of Some Novel Heterocyclic Antihyperlipidemic Agents

In-silico approach was used to select thirty molecules which are predicted to be effective against the target enzyme HMG -Co-A and the protein was downloaded from Protein Bank (PDB id-1t02). This was done by molecular docking studies against the target enzyme and the ligands. • In-silico ADME assessment and In-silico toxicity predictions were carried out to find the drug likeness property and toxicity nature of the selected 30 molecules after docking. • 30 molecules which were selected from docking score were synthesized. • The synthesised molecules are 1,2,3 triazole derivatives of Coumarin, Quinoline and Pthalimide. Thirty new molecules comprises of 14 number of 1,2,3 – triazole derivatives of Coumarin (5a-5g and 6a-6g). 14 number of 1,2,3 – triazole derivatives of Quinoline (9a-9g and 10a-10g). 2 number of 1,2,3 – triazole derivatives of Pthalimide (13a-13b). • The thirty synthesised compounds were purified by chromatography using ethyl acetate and hexane (1:2) as eluting agent. • Melting point was determined by open capillary method and are presented uncorrected. All the molecules were characterized by FT-IR,1H-NMR,13C-NMR and Mass spectra. • Based upon the docking score top four molecules were chosen for anti hyperlipidemic activity. (QMB (9b), QEB (10a), QEB (10b) and CEH(6e)). • Anti-hyperlipidemic activity was carried out by feeding high fat diet to 7 groups of six animals each and at the end of nine weeks, animals were sacrificed. • The tissues were taken for in-vivo antioxidant study. • All the synthesized compounds showed increase in HDL level of the animals as compared to the group which was administered with standard drug. • The compound reduced the body weight of the animals which are fed with high fat diet at a lower dose and also decreased the level of LDL in the blood. • The in- vivo antioxidant showed good increase in the levels of Superoxide Dismutase (SOD), Catalase (CAT), Glutathione peroxidase (GPx) and Glutathione reductase (GR) compared with that of the control group. • The stability of the ligand receptor complexes were analysed by molecular dynamic stimulation. This was performed with the top glide score ligand. The study confirmed that the ligand receptor complex was stable without any notable conformational changes during the simulation run. • At the end of the MD simulation, changes in the position and orientation of ligands in the introduced binding site was observed which indicates the usefulness of the MD simulation for optimization of the ligands into the target binding site. • In the present work, simple and efficient practical methods were adopted for the synthesis of the heterocyclics which resulted from the in-silico and the compunds were obtained in good yield. • The compounds with 1,2,3 triazoles showed good anti-hyperlipidemic activity at lower dose as compared to that of the standard. • The good profile of the molecules with the In-silico toxicity and In-silico ADME properties shows it can be taken for further studies. • The Molecular simulation method also concludes the stability of ligand -receptor is significant for the compound with 1,2,3 triazole containing quinoline nucleus QEP(10b). • The above findings have demonstrated that the compound is possibly a future drug moiety for treating hyperlipidemia

A Review of Dipeptidyl Peptidase-4 (DPP-4) and its potential synthetic derivatives in the management of Diabetes Mellitus

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a type of oral medication used to treat type 2 diabetes mellitus (T2DM). They have become increasingly popular due to their effectiveness and safety in managing the condition. DPP-4 inhibitors function by inhibiting the enzyme that breaks down the incretin hormones, namely glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These medicines efficiently raise the levels of active GLP-1 and GIP by blocking DPP-4 activity. As a result, there is an increase in the production of insulin, a decrease in the release of glucagon, and a lowering of glucose levels after a meal. Multiple clinical trials have conclusively shown that DPP-4 inhibitors effectively lower glycated hemoglobin (HbA1c) levels. Certain studies have even proved their equivalent efficacy to other anti-diabetic medications such as metformin or sulfonylureas. Furthermore, DPP-4 inhibitors possess the benefit of being weight-neutral and exhibiting a little risk of hypoglycemia. These qualities render them a compelling option for patients with type 2 diabetes mellitus who are overweight or susceptible to hypoglycemia episodes. In general, DPP-4 inhibitors are a promising therapeutic choice for the management of type 2 diabetes mellitus (T2DM), offering effective regulation of blood sugar levels with a minimal likelihood of adverse effects. Nevertheless, it is important to acknowledge some restrictions and factors to take into account, including the possibility of heightened susceptibility to pancreatitis, nasopharyngitis, and certain drug-drug combinations. Additional investigation is necessary to completely clarify the long-term safety and potential supplementary advantages of DPP-4 inhibitors

Synthesis and biological evaluation of novel small molecule bromodomain inhibitors

The confidentiality statement on each page of this thesis DOES NOT apply.Previously held under moratorium in Chemistry department (GSK) from 3rd June 2019 until 7th June 2024Epigenetics is the study of changes in gene expression without changing the primary DNA sequence. Bromodomain-containing proteins are responsible for recognising acetylated residues on histone tails, recruiting transcriptional machinery and thus facilitating gene transcription. Small molecule bromodomain inhibitors prevent this recognition, thus downregulating the transcription of pro-inflammatory cytokines which could have therapeutic effects in immuno-inflammatory diseases such as RA. A targeted approach, in which a drug is delivered selectively to target cell types associated with the disease, could minimise off-target toxicity and improve a therapeutic index. This thesis focuses on the development of an esterase sensitive motif (ESM) targeting strategy, which is selectively hydrolysed by the enzyme human carboxyesterase 1 (CES-1) to produce the biologically-active acid. Outside of the liver, this enzyme’s expression profile is limited to the mononuclear monocyte and macrophage lineages, therefore providing the opportunity to treat immuno-inflammation diseases. The investigation of two structurally differentiated series is described within this thesis. The starting point compound in the first series, in which the ESM is directed over a lipophilic groove formed by a tryptophan, proline and phenylalanine (termed the WPF shelf) suffered from high in vitro clearance (IVC) and lipophilicity. Replacement of the phenyl ring, which interacts with the WPF shelf, with five-membered heterocyclic rings was shown to be suboptimal resulting in reduced potency and poor metabolic stability (Figure 0.1). However, substitution of the six-membered ring and increasing the steric hindrance of the pyridyl core resulted in compounds with low microsomal and hepatocyte clearance (Figure 0.1). A lead molecule was identified from this series with improved physicochemical properties, and desirable potency and metabolic stability. The compound showed high selectivity for the BET family over non-BET bromodomain-containing proteins and off-targets and were shown to be substrates for CES-1. [see Figure 0.1 in thesis] The second part of this thesis focusses on the optimisation of a second structurally differentiated series with an alternative warhead, in which the ESM is directed through the ZA channel. Initial candidates showed an underlying issue with IVC. A range of substituents which acted as the shelf group were investigated. Employing the best shelf groups for IVC and replacing the phenyl ring with a pyridine or a diazine improved metabolic stability and resulted in compounds with desirable IVC profiles (Figure 0.2). Two lead molecules were identified from this series, both of which demonstrated high cellular activity and metabolic stability. They were selective for the BET family and were shown not to inhibit CYP3A4 in a time dependent manner, a common observed liability in this series. [see Figure 0.2 in thesis] Overall, work outlined in this report has taken molecules with high IVC and lipophilicity and optimised them into molecules with excellent potency, as well as desirable HLM and hepatocyte IVC and lipophilicity. Three molecules across both series were progressed into late stage cynomolgus monkey PK studies and were selected as the lead molecules for the series. Although the compounds were not progressed beyond the PK studies, they were key compounds for exemplifying that reducing cynomolgus monkey hepatocyte clearance, whilst maintaining a low lipophilicity and desirable metabolic stability, increased the oral bioavailability within cynomolgus monkeys.Epigenetics is the study of changes in gene expression without changing the primary DNA sequence. Bromodomain-containing proteins are responsible for recognising acetylated residues on histone tails, recruiting transcriptional machinery and thus facilitating gene transcription. Small molecule bromodomain inhibitors prevent this recognition, thus downregulating the transcription of pro-inflammatory cytokines which could have therapeutic effects in immuno-inflammatory diseases such as RA. A targeted approach, in which a drug is delivered selectively to target cell types associated with the disease, could minimise off-target toxicity and improve a therapeutic index. This thesis focuses on the development of an esterase sensitive motif (ESM) targeting strategy, which is selectively hydrolysed by the enzyme human carboxyesterase 1 (CES-1) to produce the biologically-active acid. Outside of the liver, this enzyme’s expression profile is limited to the mononuclear monocyte and macrophage lineages, therefore providing the opportunity to treat immuno-inflammation diseases. The investigation of two structurally differentiated series is described within this thesis. The starting point compound in the first series, in which the ESM is directed over a lipophilic groove formed by a tryptophan, proline and phenylalanine (termed the WPF shelf) suffered from high in vitro clearance (IVC) and lipophilicity. Replacement of the phenyl ring, which interacts with the WPF shelf, with five-membered heterocyclic rings was shown to be suboptimal resulting in reduced potency and poor metabolic stability (Figure 0.1). However, substitution of the six-membered ring and increasing the steric hindrance of the pyridyl core resulted in compounds with low microsomal and hepatocyte clearance (Figure 0.1). A lead molecule was identified from this series with improved physicochemical properties, and desirable potency and metabolic stability. The compound showed high selectivity for the BET family over non-BET bromodomain-containing proteins and off-targets and were shown to be substrates for CES-1. [see Figure 0.1 in thesis] The second part of this thesis focusses on the optimisation of a second structurally differentiated series with an alternative warhead, in which the ESM is directed through the ZA channel. Initial candidates showed an underlying issue with IVC. A range of substituents which acted as the shelf group were investigated. Employing the best shelf groups for IVC and replacing the phenyl ring with a pyridine or a diazine improved metabolic stability and resulted in compounds with desirable IVC profiles (Figure 0.2). Two lead molecules were identified from this series, both of which demonstrated high cellular activity and metabolic stability. They were selective for the BET family and were shown not to inhibit CYP3A4 in a time dependent manner, a common observed liability in this series. [see Figure 0.2 in thesis] Overall, work outlined in this report has taken molecules with high IVC and lipophilicity and optimised them into molecules with excellent potency, as well as desirable HLM and hepatocyte IVC and lipophilicity. Three molecules across both series were progressed into late stage cynomolgus monkey PK studies and were selected as the lead molecules for the series. Although the compounds were not progressed beyond the PK studies, they were key compounds for exemplifying that reducing cynomolgus monkey hepatocyte clearance, whilst maintaining a low lipophilicity and desirable metabolic stability, increased the oral bioavailability within cynomolgus monkeys

Studies on Some Bioactive Heterocyclic Moieties

Not availabl

Anti-angiogenic and toxicity effects of Derris trifoliata extract in zebrafish embryo

Introduction: Derris trifoliata has been traditionally used as folk for the treatment of , rheumatic joints, diarrhoea, and dysmenorrhea, and rotenoids isolated from the plant have shown to exhibit anti-cancer properties. This study aimed to assess the toxicity effects and antiangiogenic activity of extract of Derris trifoliata on zebrafish embryo model. Materials and Methods: Zebrafihs embryos were treated with aqueous extract of Derris Trifoliata to evaluate its effects on angiogenesis and zebrafish-toxicity. Angiogenic response was analyzed using whole-mount alkaline phosphatase (AP) vessel staining on 72 hours post fertilization (hpf) zebrafish embryos. Results: 1.0 mg/ml concentration was toxic to zebrafish embryos and embryos exposed to concentrations at 0.5 mg/ml and below showed some malformations. Derris trifoliata aqueous extract also showed some anti-angiogenic activity in vivo in the zebrafish embryo model wereby at high concentration inhibited vessel formation in zebrafish embryo. Conclusions: The anti-angiogenic response of extract of Derris trifoliata in zebrafish in vivo model suggest its therapeutic potential as anti-cancer agent

Synthesis and QSAR Study of Some HDL Cholesterol Increasing Quinazolinone Derivatives

We describe here an easy and efficient method to obtain S-alkylated derivatives of thio-quinazolinone using different alkylating agents via a solvent-free microwave-assisted method. The alkylated thio quinazolinones were further sequentially condensed with hydrazine hydrate and different aromatic aldehydes to get the hydrazones, which were studied for QSAR. The synthesized compounds were subjected to a prediction of biological activities. A software application (PASS) was used for this purpose. The relationship between structure and different biological activities was studied and the different derivatives were recommended for the screening of some specific activities like anti-tuberculosic, anti-mycobacterial and HDL cholesterol increasing activities