Discovery, synthesis and in combo studies of Schiff's bases as promising dipeptidyl peptidase-IV inhibitors.

Diabetes mellitus is a main global health apprehension. Macrovascular illnesses, neuropathy, retinopathy, and nephropathy are considered some of its severe hitches. Gliptins are a group of hypoglycemic agents that inhibit dipeptidyl peptidase-IV (DPP-IV) enzyme and support blood glucose-lowering effect of incretins. In the current research, synthesis, characterization, docking, and biological evaluation of fourteen Schiff's bases 5a-f and 9a-h were carried out. Compound 9f revealed the best in vitro anti-DPP-IV activity of 35.7% inhibition at a concentration of 100 µM. Compounds 9c and 9f with the highest in vitro DPP-IV inhibition were subjected to the in vivo glucose-lowering test using vildagliptin as a positive inhibitor. Vildagliptin, 9c, and 9f showed significant reduction in the blood glucose levels of the treated mice after 30 min of glucose administration. Moreover, induced fit docking showed that these derivatives accommodated the enzyme binding site with comparable docking scores. Schiff's bases can serve as promising lead for the development of new DPP-IV inhibitors.

Molecular Modeling, Synthesis and Biological Evaluation of N-Phenyl-4-Hydroxy-6-Methyl-2-Quinolone-3-CarboxAmides as Anticancer Agents.

The emergence of phosphatidylinositol 3-kinase (PI3Kα) in cancer development has accentuated its significance as a potential target for anticancer drug design. Twenty one derivatives of N-phenyl-4-hydroxy-6-methyl-2-quinolone-3-carboxamide were synthesized and characterized using NMR (1H and 13C) and HRMS. The derivatives displayed inhibitory activity against human epithelial colorectal adenocarcinoma (Caco-2) and human colon cancer (HCT-116) cell lines: compounds 8 (IC50 Caco-2 = 98 µM, IC50 HCT-116 = 337 µM) and 16 (IC50 Caco-2 = 13 µM, IC50 HCT-116 = 240.2 µM). Results showed that compound 16 significantly affected the gene encoding AKT, BAD, and PI3K. The induced-fit docking (IFD) studies against PI3Kα demonstrated that the scaffold accommodates the kinase domains and forms H-bonds with significant binding residues.

Synthesis, Biological Evaluation, and Molecular Modeling Study of Substituted Benzyl Benzamides as CETP Inhibitors.

Cardiovascular disease is the most common cause for mortality and morbidity in the developed world; its risk is inversely related to the high-density lipoprotein (HDL) cholesterol levels. Therefore, there is a great interest in developing new cholesteryl ester transfer protein (CETP) inhibitors capable of raising HDL as a novel approach for the prevention of cardiovascular disease. Herein, the synthesis and characterization of ten benzyl benzamides 8a-j that aim at CETP inhibition was performed. The in vitro CETP inhibition bioassay revealed that benzamide 8j had the best activity, with a percent inhibition of 82.2% at 10 µM concentration and an IC50 value of 1.3 µM. The docking study shows that the verified compounds accommodate the binding cleft of CETP and are enclosed by a hydrophobic lining. Furthermore, the scaffold of 8a-j matches the pharmacophoric points of CETP inhibitors, particularly in its hydrophobic and aromatic functionalities.

Chemical Synthesis, Biological Evaluation, and Cheminformatics Analysis of a Group of Chlorinated Diaryl Sulfonamides: Promising Inhibitors of Cholesteryl Ester Transfer Protein.

BACKGROUND: Hyperlipidemia is characterized by an abnormally elevated serum cholesterol, triglycerides, or both. The relationship between an elevated level of LDL and cardiovascular diseases is well-established. Cholesteryl ester transfer protein (CETP) is an enzyme that moves cholesterol esters and triglycerides between LDL, VLDL, and HDL. CETP inhibition leads to a reduction in cardiovascular disease by raising HDL and minimizing LDL. OBJECTIVE: This study synthesized ten meta-chlorinated benzene sulfonamides 6a-6j and explored their structure-activity relationship. METHODS: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and HR-MS. Moreover, cheminformatics analyses included pharmacophore mapping, LibDock studies, and cheminformatics characterization using 2-dimensional (2D) molecular descriptors and principal component analysis. RESULTS: Based on in vitro functional CETP assays, compounds 6e, 6i, and 6j demonstrated the strongest inhibitory activities against CETP, reaching 100% inhibition. The inhibitory activity of compounds 6a-6d and 6f-6h ranged from 47.5% to 96.5% at 10 µM concentration. Pharmacophore mapping results suggested CETP inhibitory action, while the docking scores and calculated binding energies predicted favoring binding at the CETP active site. Best-scoring docking poses predicted critical hydrophobic features corresponding to key interactions with His232 and Cys13. Cheminformatics analysis using 2D molecular descriptors indicated that the synthesized compounds span various physicochemical properties and drug-likeness. CONCLUSION: It was found that a chloro moiety at the ortho-position, or a nitro group at the meta and para-positions, improves the CETP inhibitory activity of synthesized analogs. Computational studies suggest the formation of stable ligand-protein complexes between compounds 6a- 6j and CETP.

Synthesis, Molecular Modeling and Biological Evaluation of Novel Trifluoromethyl Benzamides as Promising CETP Inhibitors.

BACKGROUND: Hyperlipidemia is considered a major risk factor for the progress of atherosclerosis. OBJECTIVE: Cholesteryl ester transfer protein (CETP) facilitates the relocation of cholesterol esters from HDL to LDL. CETP inhibition produces higher HDL and lower LDL levels. METHODS: Synthesis of nine benzylamino benzamides 8a-8f and 9a-9c was performed. RESULTS: In vitro biological study displayed potential CETP inhibitory activity, where compound 9c had the best activity with an IC50 of 1.03 µM. Induced-fit docking demonstrated that 8a-8f and 9a-9c accommodated the CETP active site and hydrophobic interaction predominated ligand/ CETP complex formation. CONCLUSION: Pharmacophore mapping showed that this scaffold endorsed CETP inhibitors features and consequently elaborated the high CETP binding affinity.

In vivo antihyperlipidemic activity of a new series of N-(benzoylphenyl) and N-(acetylphenyl)-1-benzofuran-2-carboxamides in rats.

A new series of N-(benzoylphenyl) and N-(acetylphenyl)-1-benzofuran-2-carboxamides (3a-3d and 4a'-4c') were synthesized. Compounds (3a, 3b, and 4a'-4c') were tested in vivo using Triton-WR-1339-induced hyperlipidemic rats as an experimental model for their hypolipidemic activity. The tested animals were divided into eight groups: control, hyperlipidemic, 3a, 3b, 4a', 4b', 4c', and bezafibrate. At a dose of 15 mg/kg, the elevated plasma triglyceride (TG) levels were significantly reduced in compounds 3b (p <0.0001) and 4c' (p <0.05) after 12 and 24 h compared to the normal control group. Furthermore, high-density lipoprotein-cholesterol levels were remarkably increased in compounds 3b (p <0.001) and 4c' (p <0.05). Meanwhile, compound 4b' slightly reduced the TG levels after 12 and 24 h. The present study demonstrated new properties of the novel series of benzofuran-2-carboxamides 3b and 4c' as potent lipid-lowering agents. It is, therefore, reasonable to assume that compounds 3b and 4c' may have a promising potential in the treatment of hyperlipidemia and coronary heart diseases.

Design, synthesis, and biological evaluation of benzylamino-methanone based cholesteryl ester transfer protein inhibitors.

Cholesteryl ester transfer protein (CETP) is a glycoprotein involved in transporting lipoprotein particles and neutral lipids between high-density lipoprotein (HDL) and low density lipoproteins (LDL) and therefore its a proper target for treating dyslipidemia and related disorders. Guided by our previously-reported pharmacophore and QSAR models for CETP inhibition, we synthesized and bioassayed a series of benzylamino-methanones. The most potent illustrated 30% CETP inhibition at 10 microM.

In-Vitro Studies on Selected Jordanian Plants as Dipeptidyl Peptidase-IV Inhibitors for Management of Diabetes Mellitus.

Diabetes mellitus is a chronic disease characterized by hyperglycemia mainly because of the absolute or relative deficiency of insulin hormone. The dipeptidyl peptidase-IV inhibitors represent a class of glucose-lowering agents potentiating the action of the incretin hormones glucagon-likepeptide-1 and glucose dependent insulinotropic polypeptide, which are secreted from the intestinal endocrine cells in response to food ingestion to stimulate insulin secretion from pancreatic beta cells. Natural products have been traditionally used for curing many diseases. In this study, in-vitro biological evaluation of the isolated compounds calotoxin, calotropin, pectolinarigenin, apigenin7-O-(3",6"-di-O-E-p-coumaroyl)-ß-glycoside and extracts of Calotropis procera, Ephedra foeminea, Artemisia herba-alba, Hylocereus undatus and Marrubium vulgare showed potential inhibitory activity, where the butanol extract of Calotropis procera was found to have 85.3% inhibition of dipeptidyl peptidase-IV at 0.2 mg/100 µL concentration.

Structure-Based Design: Synthesis, X-ray Crystallography, and Biological Evaluation of N-Substituted-4-Hydroxy-2-Quinolone-3-Carboxamides as Potential Cytotoxic Agents.

BACKGROUND: Oncogenic potential of phosphatidylinositol 3-kinase (PI3Kα) has been highlighted as a therapeutic target for anticancer drug design. OBJECTIVE: Target compounds were designed to address the effect of different substitution patterns at the N atom of the carboxamide moiety on the bioactivity of this series. METHODS: Synthesis of the targeted compounds, crystallography, biological evaluation tests against human colon carcinoma (HCT-116), and Glide docking studies. RESULTS: A new series of N-substituted- 4-hydroxy-2-quinolone-3-carboxamides was prepared and characterized by means of FT-IR, 1H and 13C NMR, and elemental analysis. In addition, the identity of the core nucleus 5 was successfully characterized with the aid of X-ray crystallography. Biological activity of prepared compounds was investigated in vitro against human colon carcinoma (HCT-116) cell line. Results revealed that these compounds inhibit cell proliferation and induce apoptosis through an increase in caspase-3 activity and a decrease in DNA cellular content. Compounds 7, 14, and 17 which have H-bond acceptor moiety on p-position displayed promising PI3Kα inhibitory activity. On the other hand, derivatives tailored with bulky and hydrophobic motifs (16 and 18) on o- and m-positions exhibited moderate activity. Molecular docking studies against PI3Kα and caspase-3 showed an agreement between the predicted binding affinity (ΔGobsd) and IC50 values of the derivatives for the caspase-3 model. Furthermore, Glide docking studies against PI3Kα demonstrated that the newly synthesized compounds accommodate PI3Kα kinase catalytic domain and form H-bonding with key binding residues. CONCLUSION: The series exhibited a potential PI3Kα inhibitory activity in HCT-116 cell line.

Benzoin Schiff Bases: Design, Synthesis, and Biological Evaluation as Potential Antitumor Agents.

BACKGROUND: Phosphoinositide 3-kinase α (PI3Kα) is an attractive target for anticancer drug design. OBJECTIVES: Target compounds were designed to probe the significance of alcohol and imine moieties tailored on a benzoin scaffold to better understand the structure activity relation (SAR) and improve their biological activity as anticancer compounds. METHODS: Chemical synthesis of the targeted compounds, biological evaluation tests against human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines, as well as Glide docking studies were employed in this investigation. RESULTS: A new series of 1,2-diphenylimino ethanol was successfully synthesized and characterized by means of FT-IR, HRMS, NMR, and by elemental analysis. Biological screening revealed that the newly synthesized compounds inhibit PI3Kα activity in human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines. Results additionally showed that these compounds exhibit selective antiproliferative activity, induce apoptosis, and suppress the VEGF production. Compounds 2b, 2d, and 2g displayed promising inhibitory activity in HCT-116 suggesting that hydrophobic and/or hydrogen bond-acceptor mediate(s) ligand-receptor interaction on o- and mpositions. Furthermore, compounds 2g, 2i, 2j, and 2h, bearing hydrophobic moiety on m- and pposition, exerted high antiproliferative activity in T47D and MCF-7 cells, whereas compound 2e showed selectivity against T47D and MCF-7. Molecular docking studies against PI3Kα and caspase-3 demonstrated a strong correlation between the predicted binding affinity (ΔGobsd) and IC50 values of prepared compounds for the caspase-3 model, implying that the cellulous inhibitory activity was caspase-3-dependent. Moreover, Glide docking against PI3Kα identified Ser774, Lys802, E849, V851, and Asp933 as key binding residues. CONCLUSION: The series exerted a potential PI3Kα inhibitory activity in human carcinoma cell lines expressing PI3Kα.

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

Glycosidases, including ß-D-glucosidase, 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-glucosidase 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 employed to select an optimal combination of pharmacophoric models and physicochemical descriptors to yield self-consistent and predictive quantitative structure-activity relationship (QSAR). Three pharmacophores emerged in the QSAR equations, suggesting the existence of more than one binding mode accessible to ligands within the ß-D-glucosidase pocket. The successful pharmacophores were complemented with strict shape constraints in an attempt to optimize their receiver-operating characteristic (ROC) curve profiles. The validity of the QSAR equations and the associated pharmacophoric models were established experimentally by the identification of several ß-D-glucosidase inhibitors retrieved via in silico search of two structural databases, namely the National Cancer Institute (NCI) list of compounds, and our in-house structural database of established drugs and agrochemicals (DAC).

Discovery of new cholesteryl ester transfer protein inhibitors via ligand-based pharmacophore modeling and QSAR analysis followed by synthetic exploration.

Cholesteryl ester transfer protein (CETP) is involved in trafficking lipoprotein particles and neutral lipids between HDL and LDL and therefore is considered a valid target for treating dyslipidemic conditions and complications. Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explore the structural requirements for potent CETP inhibitors. Two pharmacophores emerged in the optimal QSAR equation (r(2)=0.800, n=96, F=72.1, r(2)(LOO) =0.775, r(2)(PRESS) against 22 external test inhibitors=0.707) suggesting the existence of at least two distinct binding modes accessible to ligands within CETP binding pocket. The successful pharmacophores were complemented with strict shape constraints in an attempt to optimize their receiver-operating characteristic (ROC) curve profiles. The validity of our modeling approach was experimentally established by the identification of several CETP inhibitory leads retrieved via in silico screening of the National Cancer Institute (NCI) list of compounds and an in house built database of drugs and agrochemicals. Two hits illustrated low micromolar IC(50) values: NSC 40331 (IC(50)=6.5 microM) and NSC 89508 (IC(50)=1.9 microM). Active hits were then used to guide synthetic exploration of a new series of CETP inhibitors.