Dissolution enhancement of Gefitinib by solid dispersion and complexation with ß-cyclodextrins: In vitro testing, cytotoxic activity, and tablet formulation.

Cancer is the leading cause of mortality worldwide. In patients with metastatic non-small cell lung cancer, epidermal growth factor receptor (EGFR) is often overexpressed. Gefitinib (GEF), an inhibitor of EGFR, is approved for the treatment of patients with metastatic non-small cell lung cancer (NSCLC). However, the low solubility and dissolution of GEF limits its bioavailability. Numerous methods, including solid dispersion (SD) and complexation, have been reported to enhance the dissolution of poorly soluble drugs. In this study, GEF complexes were prepared using methyl-ß-cyclodextrin (MßCD) and hydroxypropyl-ß-cyclodextrin (HPßCD) in two molar ratios (1:1 and 1:2), furthermore, GEF SDs were prepared using polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and poloxamer-188(PXM) in three different ratios (1:2, 1:4 and 1:6 w/w). Dissolution studies were conducted on the prepared formulations. Dissolution results showed a 1.22-2.17-fold enhancement in drug dissolution after one hour compared to untreated GEF. Two formulations that showed higher dissolution enhancement were subsequently evaluated for in-vitro cytotoxicity and were formulated into tablets. The selected PVP-GEF (1:4 w/w) and MßCD-GEF (1:1M) formulas displayed improved cytotoxicity compared to untreated GEF. The IC50 values of the PVP-GEF and MßCD-GEF were 4.33 ± 0.66 and 4.84 ± 0.38 µM, respectively which are significantly lower (p < 0.05) than free GEF. In addition, the formulated tablets exhibited enhanced dissolution compared to pure GEF tablets. PVP-GEF SD tablets released (35.1 %±0.4) of GEF after one hour, while GEF-MßCD tablets released (42.2 % ± 0.7) after one hour. In the meantime, tablets containing pure GEF showed only 15 % ± 0.5 release at the same time. The findings of this study offer valuable insights for optimizing the dissolution and hence therapeutic capabilities of GEF while mitigating its limitations.

Bioinformatics-driven discovery of novel EGFR kinase inhibitors as anti-cancer therapeutics: In silico screening and in vitro evaluation.

Epidermal growth factor receptor EGFR inhibitors are widely used as first line therapy for the treatment of non-small-cell lung cancer (NSCLC) in patients harboring EGFR mutation. However, the acquisition of a second-site mutation (T790 M) limited the efficacy and developed resistance. Therefore, discovery and development of specific drug target for this mutation is of urgent needs. In our study we used the ChemDiv diversity database for receptor-based virtual screening to secure EGFR-TK inhibitors chemotherapeutics. We identified four compounds that bind to the ATP-binding region of the EGFR-TK using AutoDock 4.0 and AutoDock Vina1.1.2 and post-docking investigations. The ligand showed hydrophobic interactions to the hydrophobic region of the binding site and engaged in hydrogen bonding with Met793. The ligands also explored π-cation interactions between the π-system of the ligand-phenyl ring and the positive amino group of Lys745. Molecular mechanics Poisson-Boltzmann surface area MM/PBSA per-residue energy decomposition analyses revealed that Val726, Leu792, Met793, Gly796, Cys797, Leu798, and Thr844 contributed the most to the binding energy. Biological evaluation of the retrieved hit compounds showed suppressing activity against EGFR auto phosphorylation and selective apoptosis-induced effects toward lung cancer cells harboring the EGFR L858R/T790M double mutation. Our work anticipated into novel and specific EGFR-TKIs and identified new compounds with therapeutic potential against lung cancer.

Design, synthesis and molecular modeling of isatin-aminobenzoic acid hybrids as antibacterial and antibiofilm agents.

Number of factors, including newly emerging infectious diseases and an increase in multi-drug resistant microbial pathogens with particular relevance for Gram-positive bacteria, make the treatment of infectious diseases in hospital-based healthcare a major challenge in the medical community. 4-Aminobenzoic acid (PABA), has demonstrated a variety of biological actions particularly, antimicrobial activity. In our study we coupled this vitamin-like molecule with different isatin derivatives. We investigated the antibacterial activity of the synthesized Schiff's bases. The compounds showed high selective activity against Gram-positive bacteria and showed weak or no activity against both Gram-negative bacteria and fungi. Compound 2a showed highest activity against S. aureus and B. subtilis (MIC 0.09 mmol/L). Additionally, these substances exhibit strong anti-B. Subtilis biofilm formation. We were able to shed insight on the binding mode of these new inhibitors using in silico docking of the compounds in the binding sites of a 3D structure of B. subtilis histidine kinase/Walk. The binding free energy of the compound 2a to the catalytic domain walk, of histidine kinase enzyme of B. subtilis bacteria, was calculated using molecular mechanics/generalized born surface area scoring. The key residues for macromolecule-ligand binding were postulated. The optimized 3D protein-ligand binding modes shed light on the B. subtilis HK/Walk-ligand interactions that afford a means to assess binding affinity to design new HK/Walk inhibitor as antibacterial agents.

Design and synthesis of multi-functional small-molecule based inhibitors of amyloid-ß aggregation: Molecular modeling and in vitro evaluation.

Amyloid-ß1-42 (Aß42) peptide aggregate formation in the brain plays a crucial role in the onset and progression of Alzheimer's disease. According to published research, the Aß monomer's amino acid residues KLVFF (16-20) self-associate to create antiparallel ß-sheet fibrils. Small compounds can prevent self-assembly and destroy Aß fibrils by attaching to the Aß16-20 regions of Aß42. To enhance biological characteristics and binding affinity to the amyloid beta peptide, ß-sheet breaker small molecules can be developed and modified with various scaffolds. In the current study, a novel series of 2,3-disubstitutedbenzofuran derivatives was designed and created by fusing the benzofuran core of a known iron chelator, neuroprotective, and neurorestorative agent, like VK-28, with a motif found in the structure of a known muscarinic inhibitor and amyloid binding agent, like SKF-64346. Measurements of the binding affinity and in vitro aggregation inhibition of the Aß42 peptide were made using the thioflavin T (ThT) test. Using AutoDock 4.2 software, molecular docking studies of the synthesized compounds were performed on the monomer and fibril structures of amyloid beta peptide. The compounds 8a-8g exhibited strong binding energy and affinity to Aß fibrils as well as a 50%-67% reduction of the growth of Aß aggregation. Finally, the positive traits of our recently synthesized compounds make them excellent candidates for additional in vivo testing as a "ß-sheet breaking agent."

Combined Modeling Study of the Binding Characteristics of Natural Compounds, Derived from Psoralea Fruits, to ß-Amyloid Peptide Monomer.

A dysfunctional protein aggregation in the nervous system can lead to several neurodegenerative disorders that result in intracellular inclusions or extracellular aggregates. An early critical event within the pathogenesis of Alzheimer's disease is the accumulation of amyloid beta peptide within the brain. Natural compounds isolated from Psoralea Fructus (PF) have significant anti-Alzheimer effects as strong inhibitors of Aß42 aggregation. Computer simulations provide a powerful means of linking experimental findings to nanoscale molecular events. As part of this research four prenylated compounds, the active ingredients of Psoralea Fructus (PF), were studied as Aß42 accumulation inhibitors using molecular simulations modeling. In order to resolve the binding modes of the ligands and identify the main interactions of Aß42 residues, we performed a 100 ns molecular dynamics simulation and binding free energy calculations starting from the model of the compounds obtained from the docking study. This study was able to pinpoint the key amino acid residues in the Aß42 active site and provide useful information that could benefit the development of new Aß42 accumulation inhibitors.

MicroRNA-539-5p-Loaded PLGA Nanoparticles Grafted with iRGD as a Targeting Treatment for Choroidal Neovascularization.

Choroidal neovascularization (CNV) is a major cause of visual impairment that results from excessive growth of blood vessels in the eye's choroid. The limited clinical efficacy of the current therapy for this condition requires the emergence of new treatment modalities such as microRNA (miRNAs). A recent study identified microRNA-539-5p (miR-539) as an angiogenic suppressor in a CNV animal model; however, its therapeutic delivery is limited. Therefore, this study aims to formulate miR-539 in targeted nanoparticles (NPs) prepared from polylactic-co-glycolic acid (PLGA). The NPs were decorated with internalizing arginylglycylaspartic (RGD) peptide (iRGD), which specifically targets the alpha-v-beta-3 (αvß3) integrin receptor that is overexpressed in blood vessels of ocular tissue in CNV patients. The 1H NMR spectra results revealed successful conjugation of iRGD peptide into PLGA NPs. The miR-539-PLGA.NPs and miR-539-iRGD-PLGA.NPs were prepared and showed a particle size of 300 ± 3 and 306.40 ± 4 nm, respectively. A reduction in human retinal microvascular endothelial cell (HRMEC) viability was shown 48 and 72 h post transfection with miR-539 incorporated in PLGA NPs and iRGD-PLGA.NPs. iRGD-functionalized PLGA NPs caused further significant reduction in cell viability when compared with plain ones, revealing an enhancement in the NP uptake with iRGD-grafted NPs. The current study showed that miR-539-PLGA.NPs and miR-539-iRGD-PLGA.NPs are promising approaches that reduced the viability of HRMECs, suggesting their therapeutic potential in the treatment of CNV.

Enhancement of the dissolution and in-vitro activity of a new antineoplastic agent.

The cell-surface molecule CD44 plays a major role in the regulation of cancer stem cells. The CD44 inhibitor compound N'-(1-dimethylaminomethyl-2-oxoindolin-3-ylidene)-2-(benzyloxy)benzohydrazide (OYB), anticancer agent is practically insoluble in water. Hence, the solid dispersion (SD) technique was used for enhancing the dissolution of OYB. The SD of OYB was achieved using OYB:poloxamer 188 (1:7) via the fusion method. The anticancer activities of the free-OYB solution and the SD formulation (OYB-SD) were investigated in-vitro. The dissolution rate of OYB-SD (1:7) increased by 2-fold compared with the untreated drug (51.52-100% at pH 1.2 and 8.25-19.15% at pH 7 buffer). In addition, OYB-SD afforded 3-folds cytotoxic effect, against LoVo cells, compared to the untreated compound (IC50 4.72 ± 0.57 and 13.97 ± 0.90 µg/ml, respectively) and against HepG2 (∼3-fold) (4.98 ± 0.368 and 13.85 ± 1.82 µg/ml, respectively) and MCF-7 (1.4-fold) cells (15.20 ± 0.20 and 21.12 ± 0.51 µg/ml, respectively), and enhanced the apoptotic potential in LoVo cells compared with free-OYB. The improved cytotoxic activity of the drug might be attributable to the enhanced dissolution of OYB.

Design, synthesis and molecular modeling study of substituted indoline-2-ones and spiro[indole-heterocycles] with potential activity against Gram-positive bacteria.

Longstanding and firsthand infectious diseases are challenging community health threats. A new series of isatin derivatives bearing ß-hydroxy ketone, chalcone, or spiro-heterocycle moiety, was synthesized in a good yield. Chemical structures of the synthesized compounds were elucidated using spectroscopic techniques and elemental analysis. Antibacterial activities of the compounds were then evaluated in vitro and by in silico modeling. The compounds were more active against Gram-positive bacteria, Staphylococcus aureus (MIC = 0.026-0.226 mmol L-1) and Bacillus subtilis (MIC = 0.348-1.723 mmol L-1) than against Gram-negative bacteria (MIC = 0.817-7.393 mmol L-1). Only 3-hydroxy-3-(2-(2,5-dimethylthiophen-3-yl)-2-oxoethyl)indolin-2-one (1b) was found as active as imipenem against S. aureus (MIC = 0.026 mmol L-1). In silico docking of the compounds in the binding sites of a homology modeled structure of S. aureus histidine kinase-Walk allowed us to shed light on the binding mode of these novel inhibitors. The highest antibacterial activity of 1b is consistent with its highest docking score values against S. aureus histidine kinase.

Preparation, characterization, dissolution, and permeation of flibanserin - 2-HP-ß-cyclodextrin inclusion complexes.

Flibanserin (FLB), an antiserotonin drug, is used to treat women with hypoactive sexual appetite disorder. FLB shows low bioavailability (~33%) probably due to its low water solubility. The current study investigated the impact of hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and sodium lauryl sulfate (SLS) on the dissolution and permeation of FLB. HP-ß-CD-FLB inclusion complexes were prepared using physical mixing and kneading at 1:1 and 1:2 M ratios and characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffractometry. The dissolution and permeation of the complexes through a cellophane membrane were performed in, 0.1, 0.3 and 0.5% SLS in phosphate buffer (pH 6.8). Derived from the slope of the linear phase solubility diagram, the apparent stability constant (K 1:1) was 372.54 M-1. Kneading changed the crystalline form of FLB to an amorphous appearance characterized by minimal crystalline peaks, indicating successful inclusion complex formation. In addition, the HP-ß-CD-FLB inclusion complexes showed twofold increased dissolution efficiency at 6 h. The cumulative FLB amount permeated at 6 h increased from 14.1% to 21.88% and 34.56% in the presence of 0.1% and 0.3% of SLS, respectively. However, increasing SLS to 0.5% did not show an increase in FLB permeation. Therefore, the HP-ß-CD-FLB inclusion complex has an improved dissolution rate compared to FLB alone. The presence of SLS in the dissolution medium increases the dissolution rate of pure FLB and its complex with HP-ß-CD. kneaded 1:1 complex was formulated bioadhesive buccal tablets and showed enhanced drug release.

Preparation and Characterization of Two Immunogens and Production of Polyclonal Antibody with High Affinity and Specificity for Darunavir.

Darunavir (DRV) is a potent antiviral drug used for treatment of infections with human immunodeficiency virus (HIV). Effective and safe treatment with DRV requires its therapeutic drug monitoring (TDM) in patient's plasma during therapy. To support TDM of DRV, a specific antibody with high affinity is required in order to develop a sensitive immunoassay for the accurate determination of DRV in plasma. In this study, two new and different immunogens were prepared and characterized. These immunogens were the DRV conjugates with keyhole limpet hemocyanin (KLH) protein. The first immunogen (DRV-KLH) was prepared by zero-length direct linking of DRV via its aromatic amino group with the tyrosine amino acid residues of KLH by diazotization/coupling reaction. The second immunogen (G-DRV-KLH) was prepared by conjugation of the N-glutaryl derivative of DRV (G-DRV) with KLH. The 5-carbon atoms-spacing G-DRV hapten was synthesized by reaction of DRV via its aromatic amino group with glutaric anhydride. The reaction was monitored by HPLC and the chemical structure of G-DRV was confirmed by mass, 1H-NMR, and 13C-NMR spectroscopic techniques. The hapten (G-DRV) was linked to the KLH protein by water-soluble 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) coupling procedure. The pertinence of the coupling reactions of haptens to protein was confirmed, and the immunogens were characterized by ultraviolet (UV) spectrophotometry. Both DRV-KLH and G-DRV-KLH were used for the immunization of animals and the animal's antiserum that showed the highest affinity was selected. The collected antiserum (polyclonal antibody) had very high affinity to DRV (IC50 value = 0.2 ng mL-1; defining IC50 as the DRV concentration that can inhibit antibody binding by 50% of its maximum binding) and high specificity to DRV among other drugs used in the combination therapy with DRV. Cumulative results from direct and competitive enzyme-linked immunosorbent assay (ELISA) using this polyclonal antibody proved that the immunogens were highly antigenic and elicited a specific polyclonal antibody. The produced polyclonal antibody is valuable for the development of highly sensitive and selective immunoassays for TDM of DRV.

Docking studies and molecular dynamics simulations of the binding characteristics of waldiomycin and its methyl ester analog to Staphylococcus aureus histidine kinase.

Bacterial histidine kinases (HKs) are considered attractive drug targets because of their ability to govern adaptive responses coupled with their ubiquity. There are several classes of HK inhibitors; however, they suffer from drug resistance, poor bioavailability, and a lack of selectivity. The 3D structure of Staphylococcus aureus HK was not isolated in high-resolution coordinates, precluding further disclosure of structure-dependent binding to the specific antibiotics. To elucidate structure-dependent binding, the 3D structure of the catalytic domain WalK of S. aureus HK was constructed using homology modeling to investigate the WalK-ligand binding mechanisms through molecular docking studies and molecular dynamics simulations. The binding free energies of the waldiomycin and its methyl ester analog were calculated using molecular mechanics/generalized born surface area scoring. The key residues for protein-ligand binding were postulated. The structural divergence responsible for the 7.4-fold higher potency of waldiomycin than that of its ester analog was clearly observed. The optimized 3D macromolecule-ligand binding modes shed light on the S. aureus HK/WalK-ligand interactions that afford a means to assess binding affinity to design new HK/WalK inhibitors.

Cholesterol-Conjugate as a New Strategy to Improve the Cytotoxic Effect of 5-Fluorouracil on Liver Cancer: Impact of Liposomal Composition.

PURPOSE: Hepatocellular carcinoma (HCC) is a common liver malignancy, which has a low survival rate of all cancers. 5-fluorouracil (5-FU) is clinically recognized to treat HCC. However, the success of this therapy is highly limited due to rapid clearance and non- selective distribution. Cholesterol- conjugate (5-FUC) loaded liposomes proposed to facilitate the transport of 5-FUC into tumor cells via Low-Density Lipoprotein receptor (LDL receptor) that overexpressed in HCC. Thus, the aim of this study was to use 5-FUC loaded liposome as a promising strategy to combat HCC and improve the response of HCC to chemotherapy. METHODS: 5-FUC and 5-FU loaded liposomes were optimized based on Cholesterol (CHO) ratio and type of phospholipid to achieve a potential effect on HCC. Liposomes were prepared by the thin-film hydration method, and evaluated in terms of particle size, polydispersity, zeta potential, Entrapment Efficiency (EE), morphology, drug release and cytotoxicity. RESULTS: The obtained liposomes had a suitable nano-range particle size with negative zeta potential, and acceptable EE%. In vitro drug release of 5-FUC loaded liposomes showed a lower cumulative release over 24 h as compared to 5-FU loaded liposomes. 5-FUC loaded liposomes exhibited a higher in vitro cytotoxic effect as compared to the free drug and 5-FU loaded liposomes against HepG2 cell lines after 48 h via MTT assay. CONCLUSION: These results concluded that 5-FUC loaded liposomes could be used as an alternative tactic to increase the therapeutic index of 5-FU and pave the way for potential clinical applications.

1, 3, 4-Thiadiazole and 1, 2, 4-triazole-3(4 H )-thione bearing salicylate moiety: synthesis and evaluation as anti- Candida albicans

Abstract Dramatically increased occurrence of both superficial and invasive fungal infections has been observed. Candida albicans appear to be the main etiological agent of invasive fungal infections. The anti-C. albicans activity of thiosemicarbazide, 1,3,4-Thiadiazole, and 1,2,4-triazole-3(4H)-thione compounds (compounds 3-23) were investigated. The MIC values of thiadiazole and triazole derivatives 10-23 were in the range of 0.08-0.17 µmol mL-1, while that of fluconazole was 0.052 µmol mL-1. Compound 11 (5-(2-(4-chlorobenzyloxy)phenyl)-N-allyl-1,3,4-thiadiazol-2-amine) and compound 18 (5-(2-(4-chlorobenzyloxy)phenyl)-4-allyl-2H-1,2,4-triazole-3(4H)-thione) were found to be the most active compounds, with MIC values of 0.08 µmol mL-1. The newly synthesized thiadiazole and triazole compounds (compounds 10-23) showed promising anti-Candida activity. The allyl substituent-bearing compounds 11 and 18 exhibited significant anti-Candida albicans activity and showed a binding mode as well as the fluconazole x-ray structure.

Target ß-catenin/CD44/Nanog axis in colon cancer cells by certain N'-(2-oxoindolin-3-ylidene)-2-(benzyloxy)benzohydrazides.

Cell surface molecule CD44 plays a major role in regulation of cancer stem cells CSCs on both phenotypic and functional level, however chemical inhibition approach of CD44 to targets CSCs is poorly studied. Herein, we report the discovery of certain N'-(2-oxoindolin-3-ylidene)-2-(benzyloxy)benzohydrazides as a novel inhibitor of CD44. Molecular docking study showed interference of the scaffold of these compounds with ß-catenin/TCF-4 complex, building a direct relationship between CD44 inhibition and observed well-fitted binding domain. Compound 11a, most potent member elicits inhibition effect on TCF/LEF reporter activity conformed the involvement of Wnt pathway inhibition as a mechanism of action. Furthermore, the treatment by the mentioned compound leads to inhibition of embryonic transcriptional factor Nanog but not Sox2 or Oct-4 suggested specific targeted effect. Moreover, the cytotoxicity and cell cycle effect of this series seems to be dependent on CD44 expression.

Pharmacophore elucidation and molecular docking studies on phosphodiesterase-5 inhibitors.

cGMP-binding cGMP-specific PDE, PDE5 plays a key role in the hydrolysis of cyclic guanidine monophosphate. Because cGMP mediates vascular functions, a PDE5 inhibitor that elevates cGMP level is an attractive means for vasodilatation and treatment of erectile dysfunction. In this paper we report the elucidation of the common pharmacophore hypothesis of different classes of PDE5 inhibitors. Using LigandScout program, pharmacophore modelling studies were performed on prior reported potent PDE5 inhibitors with a variety of scaffolds in order to identify one common set of critical chemical features of these PDE5 inhibitors 1-52. The best pharmacophore model, model-1, characterized by four chemical features: one aromatic ring, one hydrophobe, one hydrogen acceptors and one hydrogen donor. Using Dock6 program, docking studies were performed in order to investigate the mode of binding of these compounds. The molecular docking study allowed confirming the preferential binding mode of different classes of PDE5 inhibitors inside the active site. The obtained binding mode was as same as that of vardenafil, X-ray ligand with different orientation with varied PDE5 inhibitors׳ scaffold.

Formulation and evaluation of cholesterol-rich nanoemulsion (LDE) for drug delivery potential of cholesteryl-maleoyl-5-fluorouracil.

It has been reported that cholesterol-rich nanoemulsions (LDE) can bind to low density lipoprotein (LDL) receptors which can concentrate anticancer drugs in the tissues via LDL receptor overexpression and reduced the adverse effects of the treatment. Therefore, in this study, LDE nanoemulsions of cholesteryl-maleoyl-5-fluorouracil (5-FU conjugate) were developed and evaluated in vitro. LDE nanoemulsions were prepared by high-energy emulsification technique. Developed formulations were characterized in terms of droplet size, polydispersity index, zeta potential, viscosity and refractive index. Optimized formulation (L5) was also evaluated for surface morphology using transmission electron microscopy (TEM). Developed formulations were subjected to in vitro drug release studies through dialysis membrane. The droplet size (50 nm), polydispersity index (0.109) and viscosity (32.16 cp) were found to be lowest for optimized formulation L5. The results of zeta potential indicated the stable formation of developed LDE nanoemulsions. TEM images of optimized formulation indicated non-spherical shape of droplets. About 97% of conjugate was found to be released from L5 after 24 h of study. Overall, these results indicated that developed LDE nanoemulsions could be successfully used for oral delivery of 5-FU conjugate.

Novel ethyl 1,5-disubstituted-1H-pyrazole-3-carboxylates as a new class of antimicrobial agents.

A series of pyrazole derivatives 9-22 were designed and synthesized. All the newly synthesized compounds were assayed for their antimicrobial activity against the Grampositive bacteria Staphyllococcus aureus and Bacillius subtilis and the Gram-negative bacteria Escherichia coli, Pseudomonas aeruginosa, in addition to the fungi organisms, Candida albicans, C. parapsilosis and C. tropicalis. Ethyl 5-(2,5-dimethylthiophen-3-yl)-1-phenyl-1H-pyrazole-3-carboxylate (21) (MIC(E.coli) = 0.038 µmol mL⁻¹, MIC(P. aerug.) = 0.067 µmol mL⁻¹) is nearly as active as ampicillin (MIC = 0.033 and 0.067 µmol mL⁻¹), respectively. Ethyl 5-(4-bromo-2-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylate (16) (MIC = 0.015 µmol mL⁻¹) is more active than fluconazole (0.020 µmol mL⁻¹) as a reference drug against C. parapsilosis.

Design and synthesis of new cholesterol-conjugated 5-Fluorouracil: a novel potential delivery system for cancer treatment.

Cholesterol-conjugated 5-fluorouracil prodrugs were designed to be carried in vivo via low density lipoproteins (LDL) and subsequently undergo LDL-receptor-mediated internalisation into cancer cells. In vivo anti-cancer evaluation was performed using 5-fluorouracil-cholesterol conjugate in a mouse model. The obtained prodrugs were more potent than 5-fluorouracil control drug at the same 5-fluorouracil content (3 mg·kg-1).

In silico studies of quinoxaline-2-carboxamide 1,4-di-n-oxide derivatives as antimycobacterial agents.

Molecular modelling studies were performed on some previously reported novel quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives (series 1-9). Using the LigandScout program, a pharmacophore model was developed to further optimize the antimycobacterial activity of this series of compounds. Using the Dock6 program, docking studies were performed in order to investigate the mode of binding of these compounds. The molecular modeling study allowed us to confirm the preferential binding mode of these quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives inside the active site. The obtained binding mode was as same as that of the novobiocin X-ray structure.

Targeting cancer using cholesterol conjugates.

Conjugation of cholesterol moiety to active compounds for either cancer treatment or diagnosis is an attractive approach. Cholesterol derivatives are widely studied as cancer diagnostic agents and as anticancer derivatives either in vitro or in vivo using animal models. In largely growing studies, anticancer agents have been chemically conjugated to cholesterol molecules, to enhance their pharmacokinetic behavior, cellular uptake, target specificity, and safety. To efficiently deliver anticancer agents to the target cells and tissues, many different cholesterol-anticancer conjugates were synthesized and characterized, and their anticancer efficiencies were tested in vitro and in vivo.