Fluorinated Diaryl Sulfonamides: Molecular Modeling, Synthesis, and In Vitro Validation as New CETP Inhibitors.

BACKGROUND: Hyperlipidemia, a cardiovascular disease risk factor, is characterized by a rise in low-density lipoprotein (LDL), triglycerides and total cholesterol, and a decrease in high-density lipoprotein (HDL). Cholesteryl ester transfer protein (CETP) enables the transfer of cholesteryl ester from HDL to LDL and very low-density lipoprotein. OBJECTIVE: CETP inhibition is a promising approach to prevent and treat cardiovascular diseases. By inhibiting lipid transport activity, it increases HDL levels and decreases LDL levels. METHOD: Herein, diaryl sulfonamides 6a-6g and 7a-7g were prepared, and the structure of these compounds was fully determined using different spectroscopic techniques. RESULTS: These compounds underwent biological evaluation in vitro and showed different inhibitory activities against CETP; 100% inhibitory activity was observed for compounds 7a-7g, while activities of compounds 6a-6g ranged up to 42.6% at 10 µM concentration. Pharmacophore mapping agreed with the bioassay results where the four aromatic ring compounds 7a-7g possessed higher fit values against Hypo4/8 and the shape-complemented Hypo4/8 in comparison to compounds 6a-6g. CONCLUSION: Docking of the synthesized compounds using libdock and ligandfit engines revealed that compounds 7a-7g formed п-п stacking and hydrophobic interactions with the binding pocket, while compounds 6a-6g missed these hydrophobic interactions with amino acids Leu206, Phe265, and Phe263.

Lycopene as a Potential Bioactive Compound: Chemistry, Extraction, and Anticancer Prospective.

Lycopene, a potential bioactive agent, is a non-pro-vitamin A carotenoid recognized as a potent antioxidant. It is extracted from plants like tomatoes, watermelons, red carrots and papayas and has remarkable health benefits. A significant amount of research has been assisted to date to establish the anticancer activity of lycopene. Our review enhances information about the promising anticancer potential of this compound. The biological activity of lycopene has been described in several studies in regard to pancreatic, breast, prostate, liver, gastric, ovarian, kidney, skin, intestine, brain and spinal cord cancers. Lycopene resists cancer by inhibition of apoptosis, induction of cell proliferation, cell invasion, cell cycle development, metastasis and angiogenesis. The mechanisms of anticancer action of lycopene are attributed to the management of certain signal transduction pathways, such as modulation of insulin-like growth factors system, PI3K/Akt pathway, modification of important gene expression, inhibit the activity of sex steroid hormones, and the conversation of mitochondrial behavior. Hence, this review focuses on current knowledge of sources, extraction techniques, and chemistry of lycopene, as well as the prospective mechanisms of action related with its anticancer activity. Also, it summarizes the background information about lycopene and the most current research with consideration to its aspect in treating several types of cancer together with future directions.

Trifluoromethylated Aryl Sulfonamides as Novel CETP Inhibitors: Synthesis, Induced Fit Docking, Pharmacophore Mapping and Subsequent In vitro Validation.

BACKGROUND: Cardiovascular disease is one of the leading causes of death. Atherosclerosis causes arterial constriction or obstruction, resulting in acute cardiovascular illness. Cholesteryl ester transfer protein (CETP) facilitates reverse cholesterol transport. It supports the transfer of cholesteryl ester from HDL to LDL and VLDL. Inhibition of CETP by drugs limits cardiovascular disease by decreasing LDL and increasing HDL. OBJECTIVES: In this study, fourteen trifluoromethyl substituted benzene sulfonamides 6a-6g and 7a-7g were prepared. METHODS: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR and HR-MS. They were in vitro tested to estimate their CETP inhibitory activity. RESULTS: In vitro biological evaluation showed that compounds 7d-7f had the highest inhibitory activity with 100% inhibition, while the inhibition observed by compounds 6a-6g, 7a-7c and 7g ranged from 2%-72% at 10 µM concentration. It was found that the addition of a fourth aromatic ring significantly improved the activity, which may be due to the hydrophobic nature of CETP. Also, the presence of ortho-chloro, meta-chloro and para-methyl substituents results in high inhibitory activity. CONCLUSION: The induced fit docking studies revealed that hydrophobic interaction guided ligand/ CETP binding interaction in addition to H-bond formation with Q199, R201, and H232. Furthermore, pharmacophore mapping demonstrated that this series satisfies the functionalities of the current CETP inhibitors.

Phenanthridine Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Design, Synthesis and Biological Evaluation.

BACKGROUND: Diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia over a prolonged period, disturbance of fat, protein, and carbohydrate metabolism, resulting from defective insulin secretion, insulin action or both. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are relatively a new class of oral hypoglycemic agents that reduce the deterioration of gutderived endogenous incretin hormones secreted in response to food ingestion to stimulate the secretion of insulin from beta cells of the pancreas. OBJECTIVE: In this study, synthesis, characterization, and biological assessment of twelve novel phenanthridine sulfonamide derivatives 3a-3l as potential DPP-IV inhibitors were carried out. The target compounds were docked to study the molecular interactions and binding affinities against the DPP-IV enzyme. METHODS: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and MS. Quantum-polarized ligand docking (QPLD) was also performed. RESULTS: In vitro biological evaluation of compounds 3a-3l reveals comparable DPP-IV inhibitory activities ranging from 10%-46% at 100 µM concentration, where compound 3d harboring ortho- fluoro moiety exhibited the highest inhibitory activity. QPLD study shows that compounds 3a-3l accommodate DPP-IV binding site and form H-bonding with the R125, E205, E206, S209, F357, R358, K554, W629, S630, Y631, Y662, R669, and Y752 backbones Conclusion: In conclusion, phenanthridine sulfonamides could serve as potential DPP-IV inhibitors that require further structural optimization in order to enhance their inhibitory activity.

Synthesis and Molecular Modeling of Novel 3,5-Bis(trifluoromethyl) benzylamino Benzamides as Potential CETP Inhibitors.

BACKGROUND: There is an alarming spread of cases of lipid disorders in the world that occur due to harmful lifestyle habits, hereditary risk influences, or as a result of other illnesses or medicines. Cholesteryl Ester Transfer Protein (CETP) is a 476-residue lipophilic glycoprotein that helps in the transport of cholesteryl ester and phospholipids from the atheroprotective HDL to the proatherogenic LDL and VLDL. Inhibition of CETP leads to elevation of HDL cholesterol and reduction of LDL cholesterol and triglycerides; therefore, it is considered a good target for the treatment of hyperlipidemia and its comorbidities. OBJECTIVE: In this research, synthesis, characterization, molecular modeling, and biological evaluation of eight 3,5-bis(trifluoromethyl)benzylamino benzamides 9a-d and 10a-d were carried out. METHODS: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and HR-MS. They were biologically tested in vitro to estimate their CETP inhibitory activity. RESULTS: These compounds offered inhibitory effectiveness ranging from 42.2% to 100% at a concentration of 10 µM. Compounds bearing unsubstituted three aromatic rings (9a) or ortho-CF3 substituted (9b) were the most effective compounds among their analogs and showed IC50 values of 1.36 and 0.69 µM, respectively. The high docking scores of 9a-d and 10a-d against 4EWS imply that they might be possible CETP inhibitors. Pharmacophore mapping results demonstrate that the series approves the fingerprint of CETP active inhibitors and therefore explains their high binding affinity against CETP binding site. CONCLUSION: This work concludes that 3,5-bis(trifluoromethyl)benzylamino benzamides can serve as a promising CETP inhibitor lead compound.

Cholesteryl ester transfer protein inhibitory oxoacetamido-benzamide derivatives: Glide docking, pharmacophore mapping, and synthesis

Abstract Dyslipidemia is an abnormal lipid profile associated with many common diseases, including coronary heart disease and atherosclerosis. Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein that is responsible for the transfer of cholesteryl ester from high-density lipoprotein athero-protective particles to pro-atherogenic very low-density lipoprotein and low-density lipoprotein particles. The requirement for new CETP inhibitors, which block this process has driven our current work. Here, the synthesis as well as the ligand-based and structure-based design of seven oxoacetamido-benzamides 9a-g with CETP inhibitory activity is described. An in vitro study demonstrated that most of these compounds have appreciable CETP inhibitory activity. Compound 9g showed the highest inhibitory activity against CETP with an IC50 of 0.96 µM. Glide docking data for compounds 9a-g and torcetrapib provide evidence that they are accommodated in the CETP active site where hydrophobic interactions drive ligand/CETP complex formation. Furthermore, compounds 9a-g match the features of known CETP active inhibitors, providing a rationale for their high docking scores against the CETP binding domain. Therefore, these oxoacetamido-benzamides show potential for use as novel CETP inhibitors

Piperazine sulfonamides as DPP-IV inhibitors: Synthesis, induced-fit docking and in vitro biological evaluation.

Diabetes mellitus is a chronic illness that needs persistent medical attention and continuous patient self-management to avoid acute complications. Dipeptidyl peptidase-IV (DPP-IV) inhibitors minimize glucagon and blood glucose levels by increasing the incretin levels, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic poly-peptide (GIP), leading to insulin secretion from pancreatic beta cells. In the present study, nine 1,4-bis(phenylsulfonyl) piperazine derivatives 1a-i were synthesized and identified using 1H NMR, 13C NMR, MS and IR spectroscopies. These compounds were tested in vitro and showed inhibitory activity ranging from 11.2 to 22.6 % at 100 µmol L-1 concentration. Piperazine sulfonamide derivatives were found to be promising DPP-IV inhibitors, where the presence of electron-withdrawing groups such as Cl (1a-c) improved the activity of the compounds more than electron-donating groups such as CH3 ( 1d-f) at the same position. Additionally, meta-substitution is disfavored (1b, 1e, 1g). Induced-fit docking studies suggested that the targeted compounds 1a-i occupy the binding domain of DPP-IV and form H-bonding with the backbones of R125, E205, E206, F357, K554, W629, Y631, Y662 and R669.

Synthesis, Biological Evaluation, and QPLD Studies of Piperazine Derivatives as Potential DPP-IV Inhibitors.

BACKGROUND: Diabetes mellitus is a serious global health issue, currently affecting 425 million people and is set to affect over 690 million people by 2045. It is a chronic disease characterized by hyperglycemia due to relative or absolute insulin hormone deficiency. Dipeptidyl peptidase- IV (DPP-IV) inhibitors are hypoglycemic agents augmenting the action of the incretin hormones that stimulate insulin secretion from the pancreatic beta cells. OBJECTIVE: In this study, synthesis and biological evaluation of seven piperazine derivatives 3a-g was carried out. METHODS: The synthesized molecules were characterized using proton-nuclear magnetic resonance, carbon-nuclear magnetic resonance, infrared spectroscopy and mass spectrometry. RESULTS: In vitro biological evaluation study showed comparable DPP-IV inhibitory activity for the targeted compounds ranging from 19%-30% at 100 µM concentration. Furthermore, the in vivo hypoglycemic activity of 3d was evaluated using streptozotocin-induced diabetic mice. It was found that compound 3d significantly decreased the blood glucose level when the diabetic group treated with 3d was compared to the control diabetic group. Quantum-Polarized Ligand Docking (QPLD) studies demonstrate that 3a-g fit the binding site of DPP-IV enzyme and form H-bonding with the backbones of R125, E205, E206, K554, W629, Y631, Y662, R669, and Y752. CONCLUSION: Piperazine derivatives were successfully found to be new scaffolds as potential DPP-IV inhibitors.

Synthesis of Novel Benzimidazole-2-carboxamide Derivatives and in Vivo Antihyperlipidemic Activity Evaluation.

Hyperlipidemia is known as an elevation of plasma lipid components. It contributes significantly to atherosclerosis which is one of the most important causative factors in cardiovascular diseases. Agents that cause a dramatic decrease in serum lipid levels are of great value in the treatment of cardiovascular diseases. For this purpose, a new series of benzimidazole propyl carboxamide benzophenone derivatives have been synthesized (7, 8, and 9). These compounds were tested in vivo to evaluate their potential hypolipidemic activity using Triton WR-1339 induced hyperlipidemic rats. All the synthesized compounds have proved to be highly biologically active, with compound 9 being the most active derivative.

Synthesis, Structural Characterization and Docking Studies of Sulfamoyl- Phenyl Acid Esters as Dipeptidyl Peptidase-IV Inhibitors.

BACKGROUND: Diabetes mellitus is a major worldwide health concern that has several serious complications including retinopathy, neuropathy, nephropathy and macrovascular diseases. OBJECTIVE: Dipeptidyl peptidase-IV (DPP-IV) inhibitors, gliptins, are a new class of antidiabetic agents that potentiate the action of incretins in decreasing the blood glucose levels. METHODS: In the present study, synthesis and characterization of a series of ten N4-sulfonamido-acrylic and phthalamic acid methyl esters (3a-e and 5a-e) were achieved. RESULTS: In vitro anti-DPP-IV activity of the synthesized compounds was evaluated, where compound 3b demonstrated the best activity with a % inhibition of 41.7 at 10 µM concentration and an IC50 of 23.9 µM. Moreover, Glide docking experiments revealed that our targeted compounds accommodate the binding site of DPP-IV and tend to form H-bonding with the backbones of R125, E206, S209, D545, K554, W629, Y631, and G632. CONCLUSION: Modeling findings recommend the attachment of bulky hydrophobic group on the ester side of the structure in addition to harboring extra aromatic rings that might be beneficial for better binding interaction and biological activity.

Molecular Docking and Pharmacophore Modeling Studies of Fluorinated Benzamides as Potential CETP Inhibitors.

BACKGROUND: Hyperlipidemia is one of the most common chronic diseases worldwide. Cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein that facilitates the transfer of cholesteryl ester from the atheroprotective high-density lipoprotein (HDL) to the proatherogenic low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). METHODS: In this work, synthesis and characterization of five fluorinated 3-benzylamino benzamides 8a-8c, 13a and 13b that target CETP activity were carried out. RESULTS: Benzamides 8b and 8a showed the highest CETP inhibitory activities with an IC50 of 0.75 µM and 4.1 µM respectively. It was found that the presence of p-OCF3 group (as in 8a-8c) enhances CETP inhibitory activity more than p-OCF2CHF2 (as in 13a and 13b) which could be attributed to the bulkiness of the tetrafluoroethoxy group hindering their proper orientation in the binding domain. Additionally m-F derivatives were found to have higher activity against CETP than p-F ones leaving the o-F analogues with the weakest anti-CETP bioactivity. CONCLUSION: Ligand-based and structure-based drug design strategies confirm that hydrophobic interaction mediates ligand/protein complex formation and explains the activity of our verified molecules.

Exploring Natural Products as a Source for Antidiabetic Lead Compounds and Possible Lead Optimization.

BACKGROUND: Natural products are characterized by their chemical diversity and being a good source of a range of bioactive structures including antidiabetic compounds. Diabetes mellitus (DM) is considered a major worldwide health concern. Rational drug design has been widely accomplished, to discover and optimize innovative leads for different molecular targets of type 2 DM including α-glucosidase, PPARγ, DPP-IV, PTP1B, AR, GSK-3ß, 11ß-HSD1, GK, etc. OBJECTIVE: This review illustrates the potential of natural products as a rich source of lead compounds for antidiabetic drug discovery with some examples of computational studies carried out to determine the possible molecular target, structure activity relationship, and further optimization chances. CONCLUSION: Natural products will remain an attractive source for researchers to explore their therapeutic potential against DM. Guided by the computational studies; systematic lead optimization via structural modifications will speed up the generation of potential new clinical candidates for the treatment of type 2 DM.

Molecular modeling based approach, synthesis, and cytotoxic activity of novel benzoin derivatives targeting phosphoinostide 3-kinase (PI3Kα).

The oncogenic potential of phosphatidylinositol 3-kinase (PI3Kα) has made it an attractive target for anticancer drug design. In this work, we describe our efforts to optimize the lead PI3Kα inhibitor 2-hydroxy-1,2-diphenylethanone (benzoin). A series of 2-oxo-1,2-diphenylethyl benzoate analogs were identified as potential PI3Kα inhibitors. Docking studies confirmed that the aromatic interaction is mediating ligand/protein complex formation and identified Lys802 and Val851 as H-bonding key residues. Our biological data in human colon carcinoma HCT116 showed that the structure analogs inhibited cell proliferation and induced apoptosis.

Design, Synthesis and Biological Evaluation of N4-Sulfonamido-Succinamic, Phthalamic, Acrylic and Benzoyl Acetic Acid Derivatives as Potential DPP IV Inhibitors.

As incidence rate of type II diabetes mellitus continues to rise, there is a growing need to identify novel therapeutic agents with improved efficacy and reduced side effects. Dipeptidyl peptidase IV (DPP IV) is a multifunctional protein involved in many physiological processes. It deactivates the natural hypoglycemic incretin hormone effect. Inhibition of this enzyme increases endogenous incretin level, incretin activity and should restore glucose homeostasis in type II diabetic patients making it an attractive target for the development of new antidiabetic drugs. One of the interesting reported anti- DPP IV hits is Gemifloxacin which is used as a lead compound for the development of new DPP IV inhibitors. In the current work, design and synthesis of a series of N4-sulfonamido-succinamic, phthalamic, acrylic and benzoyl acetic acid derivatives was carried out. The synthesized compounds were evaluated for their in vitro anti-DPP IV activity. Some of them have shown reasonable bioactivity, where the most active one 17 was found to have an IC50 of 33.5 µM.

Discovery of new antifungal leads via pharmacophore modeling and QSAR analysis of fungal N-myristoyl transferase inhibitors followed by in silico screening.

N-Myristoyl transferase is an essential enzyme for fungal growth and survival. The continuous interest in the development of new antifungal agents prompted recent interest in developing new potent inhibitors of fungal N-myristoyl transferase. In this context, we combined pharmacophore and QSAR modeling to explore the structural requirements for potent N-myristoyl transferase inhibitors employing 55 known N-myristoyl transferase ligands. Four binding pharmacophore models emerged in the optimal QSAR equations (R(2)(44) = 0.81-0.83, F-statistic = 47.89-58.83, r(2)(L00)= 0.77-0.80, against 11 external test inhibitors = 0.61-0.71). The successful pharmacophores were complemented with exclusion spheres to optimize their receiver operating characteristic curve profiles. The QSAR equations and their associated pharmacophore models were validated by the identification and experimental evaluation of new promising antifungal leads retrieved from the NCI database and our in-house-built database of established drugs and agrochemicals.

Discovery of new ß-D-galactosidase inhibitors via pharmacophore modeling and QSAR analysis followed by in silico screening.

Glycosidases, including ß-D-galactosidase, are involved in a variety of metabolic disorders, such as diabetes, viral or bacterial infections, and cancer. Accordingly, we were prompted to find new ß-D-galactosidase inhibitors. Towards this end, we scanned the pharmacophoric space of this enzyme using a set of 41 known inhibitors. Genetic algorithm and multiple linear regression analyses were used to select an optimal combination of pharmacophoric models and physicochemical descriptors to yield self-consistent and predictive quantitative structure-activity relationship (QSAR). Five pharmacophores emerged in the QSAR equations suggesting the existence of more than one binding mode accessible to ligands within ß-D-galactosidase pocket. The successful pharmacophores were complemented with strict shape constraints in an attempt to optimize their receiver-operating characteristic curve profiles. The validity of the QSAR equations and the associated pharmacophoric models were experimentally established by the identification of several ß-D-galactosidase inhibitors retrieved via in silico search of two structural databases: the National Cancer Institute list of compounds and our in house built structural database of established drugs and agrochemicals.