Reema Abu Khalaf

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.

Discovery of new β- d -glucosidase inhibitors via pharmacophore modeling and QSAR analysis followed by in silico screening

Glycosidases, including β-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 β-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 β-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 β-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 β-D-galactosidase inhibitors via pharmacophore modeling and QSAR analysis followed by in silico screening.

Glycosidases, including β‐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 β‐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 β‐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 β‐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.

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.

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 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 previosuly-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 μM.

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.

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.

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.

Ligand-Based Drug Design: Synthesis and Biological Evaluation of Substituted Benzoin Derivatives as Potential Antitumor Agents

BACKGROUND Phosphoinositide 3-kinase α (PI3Kα) has emerged as a promising target for anticancer drug design. OBJECTIVES Target compounds were designed to investigate the effect of the p-OCH3 motifs on ligand/PI3Kα complex interaction and antiproliferative activity. METHODS Synthesis of the proposed compounds, biological examination tests against human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines, along with Glide docking studies. RESULTS A series of 1,2-bis(4-methoxyphenyl)-2-oxoethyl benzoates was synthesized and characterized by means of FT-IR, 1H and 13C NMR, and by elemental analysis. Biological investigation demonstrated that the newly synthesized compounds exhibit antiproliferative activity in human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines possibly via inhibition of PI3Kα and estrogen receptor alpha (ERα). Additionally, results revealed that these compounds exert selective inhibitory activity, induce apoptosis, and suppress VEGF production. Compound 3c exhibited promising antiproliferative activity in HCT-116 interrogating that hydrogen bond-acceptor mediates ligand/PI3Kα complex formation on m- position. Compounds 3e and 3i displayed high inhibitory activity in MCF-7 and T47D implying a wide cleft discloses the o-attachment. Furthermore, compound 3g exerted selective inhibitory activity against T47D. Glide docking studies against PI3Kα and ERα demonstrated that the series accommodate binding to PI3Kα and/or ERα. CONCLUSION The series exhibited a potential antitumor activity in human carcinoma cell lines encoding PI3Kα and/or ERα.