Ghassan Abu Sheikha

Elaborate ligand-based pharmacophore exploration and QSAR analysis guide the synthesis of novel pyridinium-based potent β-secretase inhibitory leads

Beta-secretase (BACE) inhibitors have potential as anti-Alzheimers disease treatments prompting us to explore the pharmacophoric space of 129 known BACE inhibitors. QSAR analysis was employed to select optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of explaining bioactivity variation (r(2)=0.88, F=60.48, r(LOO)(2)=0.85, r(PRESS)(2) against 25 external test inhibitors=0.71). We were obliged to use ligand efficiency as the response variable because the logarithmic transformation of bioactivities failed to access self-consistent QSAR models. Three pharmacophoric models emerged in the successful QSAR equation suggesting at least three binding modes accessible to ligands within BACE binding pocket. QSAR equation and pharmacophoric models were validated through ROC curves and were employed to guide synthesis of novel pyridinium-based BACE inhibitors. The best inhibitor illustrated an IC(50) value of 1.0 microM against BACE.

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.

Synthesis and anti-hyperlipidemic evaluation of N‑(benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide derivatives in Triton WR-1339-induced hyperlipidemic rats.

The lipid-lowering activity of a series of novel N-(benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide derivatives has been studied in Triton WR-1339-induced hyperlipidemia in rats. The test animals were divided into four groups: control, hyperlipidemic, compound + 4% DMSO [C1: N-(2-benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide (1), C2: N-(3-benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide (2), C3: N-(4-benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide (3)]-treated and bezafibrate (BF)-treated. At a dose of 15 mg/Kg body weight, compounds 2, 3 and BF significantly reduced elevated plasma triglycerodes levels after 12 h. Moreover, high density lipoprotein-cholesterol levels were significantly increased in all treated groups after 12 h compared to the hyperlipidemic control group, except for C1 which was inactive. In sum, it may be stated that the results of the present study demonstrated new properties of some N-(benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide derivatives as potent lipid lowering agents and these beneficial activities may contribute to their cardioprotective and antiatherosclerotic role.

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.

Antihyperlipidemic Properties of Novel N-(Benzoylphenyl)-5-substituted-1H-indole-2-carboxamides in Triton WR-1339-Induced Hyperlipidemic Rats

In the search for new potential antihyperlipidemic agents, the present study focuses on the synthesis of novel N-(benzoylphenyl)-5-substituted-1H-indole-2-carboxamides (compounds 8-12, 15, 16, 18) and investigating their antihyperlipidemic activity using Triton WR-1339-induced hyperlipidemic rats as an experimental model. Hyperlipidemia was developed by intraperitoneal injection of Triton WR-1339 (250 mg/kg body weight). The tested animals were divided into normal control (NCG), hyperlipidemic (HG), compound 8, 9, 15, 16, 18- and bezafibrate treated groups. At a dose of 15 mg/kg body weight, compounds 9, 16, 18 and bezafibrate (100 mg/kg) significantly (p < 0.0001) reduced elevated plasma triglycerides levels after 12 h compared to the hyperlipidemic control group. However, only the group treated with compounds 9, 16 and 18 showed an obviously significant (p < 0.001) reduction in plasma total cholesterol levels after 12 h compared to the hyperlipidemic control group. Moreover, high density lipoprotein-cholesterol levels were significantly (p < 0.0001) increased in all treated groups after 12 h compared to the hyperlipidemic control group, except for compounds 8 and 15 which revealed inactive. It is therefore reasonable to assume that compounds 9, 16 and 18 may have potential in the treatment of hyperlipidemia.

Pharmacological evaluation of novel indole-2-carboxamides as potent lipid-lowering agents in Triton-WR-1339-induced hyperlipidemic rats.

The lipid-lowering effects of two novel antihyperlipidemic agents, BMI2C [N-(4-benzoylphenyl)- 5-methoxy-1H-indole-2-carboxamide] and DDMI2C [N-(9,10-dihydro-9,10-dioxoanthracen- 2-yl)-5-methoxy-1H-indole-2-carboxamide], were studied using hyperlipidemic rats as an experimental model; hyperlipidemia was developed by intraperitoneal injection of Triton WR-1339 (200 mg/kg body weight). At a dose of 15 mg/kg body weight, BMI2C and DDMI2C signifi cantly reduced elevated plasma triglyceride levels after 7 and 24 h. Furthermore, BMI2C and DDMI2C significantly reduced elevated plasma total cholesterol levels after 24 h. Interestingly, high-density lipoprotein-cholesterol levels were significantly increased in all treated groups. These findings indicate that the two studied novel compounds have a promising potential in the treatment of hyperlipidemia and atherosclerosis

Novel Derivatives of 1,3-Dimethyl-5-methylenebarbituric Acid

The ability of the pyridinium adduct of 1,3-dimethyl-5-methylenebarbituric acid (2) to undergo nucleophilic substitution reaction has been examined. Various types of nucleophiles, including cyanide, barbiturate, sulfide anions and 1,2-bis(diphenylphosphino)ethane substitute the pyridinium fragment in 2 leading to synthesis of new organic derivatives.

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.

Some sulfonamide drugs inhibit ATPase activity of heat shock protein 90: investigation by docking simulation and experimental validation

Eight selected sulfonamide drugs were investigated as inhibitors of heat shock protein 90 (Hsp90). The investigation included simulated docking experiments to fit the selected compounds within the binding pocket of Hsp90. The selected molecules were found to readily fit within the ATP-binding pocket of Hsp90 in low-energy poses. The sulfonamides torsemide, sulfathiazole, and sulfadiazine were found to inhibit the ATPase activity of Hsp90 with IC50 values of 1.0, 2.6, and 1.5 μM, respectively. Our results suggest that these well-established sulfonamides can be good leads for subsequent optimization into potent Hsp90 inhibitors.

Computer-aided design, synthesis, and biological evaluation of new indole-2-carboxamide derivatives as PI3Kα/EGFR inhibitors

Structure-based drug design and molecular modeling were employed to identify a new series of indole-2-carboxamides as potential anticancer agents. These compounds were synthesized and characterized with the aid of several spectroscopic techniques, such as FT-IR, NMR, and mass spectrometry as well as by elemental analysis. Molecular docking studies confirmed that the newly synthesized compounds accommodate PI3Kα and EGFR kinase catalytic sites and form H-bonding with the key binding residues. The antitumor activity of these new compounds against an array of cancer cell lines (human colon carcinoma (HCT116), leukemia (K562), and breast cancer (MDA231) was evaluated. Results revealed that these compounds were selective against the kinase domain, and none of them showed any inhibitory activity against K562. In addition, results showed that compound 13 exhibited high potency in HCT116 and MDA231 with IC50 values of 19 and 15μM, respectively. Our findings recommend that further optimization of this series would be beneficial for colon and breast cancer treatment.