Samy M. Ibrahim

Synthesis and antiviral activity of new pyrazole and thiazole derivatives

New N-acetyl (5-8) and N-thiocarbamoyl (9-12) derivatives of 4,5-dihydropyrazole were synthesized starting from alpha,beta-unsaturated ketones under the effect of hydrazine hydrate and thiosemicarbazide, respectively. N-Thiocarbamoylpyrazole derivatives (9-12) were cyclized using either ethyl bromoacetate or phenacyl bromides to afford the novel pyrazolothiazol-4(5H)-ones (13-16) or pyrazolothiazoles (17-24). The antiviral activity for such novel compounds against a broad panel of viruses in different cell cultures revealed that N-acetyl 4,5-dihydropyrazole 7 was the only active one at subtoxic concentrations against vaccinia virus (Lederle strain) in HEL cell cultures with a 50% effective concentration (EC(50)) value of 7 microg/ml.

Synthesis of new benzotriazepin-5(2H)-one derivatives of expected antipsychotic activity

A new series of 3,4-dihydro-1H-benzo[e][1,2,4]triazepin-5(2H)-one derivatives were synthesized by cyclocondensation of benzohydrazides (II, IX), derived from the reaction of N-methyl-isatoic anhydride with phenyl hydrazine and isonicotinic acid hydrazide, respectively, with formaldehyde, aromatic aldehydes in acidic medium or with carbon disulfide in alkaline medium, the last reaction was only carried out with benzohydrazide II. Benzotriazepinone derivatives IV,Va–h,VI, and XI were subjected to ptosis test using clozapine as a reference drug to evaluate their antipsychotic activity. It was found that 2-thioxobenzotriazepinone VI had the same antipsychotic activity as reference drug clozapine but with lesser side effects whereas it showed nonsignificant CNS depressant activity upon using forced swim pool test as well as no neurotoxicity when tested in mice using rotarod or horizontal screen tests.Graphical AbstractA new series of benzotriazepin-5(2H)-ones (IV,Va–h, VI, and XI) were prepared starting from isatoic anhydride and their antipsychotic activity revealed that 2-thioxobenzotriazepinone VI was superior to the reference drug clozapine.

Synthesis of New 2,3‐Dihydroquinazolin‐4(1H)‐one Derivatives for Analgesic and Anti‐inflammatory Evaluation

Starting from isatoic anhydrides, several new 2,3‐dihydroquinazolin‐4(1H)‐one derivatives bearing chalcone or pyrazole or thiazole moieties at the third position were synthesized. The analgesic and anti‐inflammatory activities for most compounds were studied at a dose level of 50 mg/kg via the acetic‐acid‐induced writhing‐response method and carrageenan‐induced edema method, respectively. The study showed that the chalcones bearing a 4‐chlorophenyl group 4c or 4‐nitrophenyl group 4b were the most active ones as analgesics. Both chalcone 4c and N‐phenyl pyrazole bearing 4‐methoxy phenyl group 5b showed a higher anti‐inflammatory activity than celecoxib but still lower than that of diclofenac sodium. Moreover, the chalcone 4c has nearly the same ulcerogenic index as the selective cyclooxygenase‐2 inhibitor celecoxib.

Design, synthesis and preliminary antiviral screening of new N-phenylpyrazole and dihydroisoxazole derivatives

A new series of N-phenylpyrazoles and dihydroisoxazles was synthesized starting from α,β-unsaturated ketones in basic media using phenyl hydrazine and hydroxylamine HCl, respectively. Antiviral evaluation of the target compounds revealed that the dihydroisoxazole derivatives have promising antiviral activity against hepatitis A virus and herpes simplex virus type 1.

Synthesis and Biological Screening of New Derivatives of 2,3-dihydroquinazolin-4(1H)-one and Benzotriazepin- 5(2H)-one for Central NervousSystem Activity

A new syntheses of novel series of 2,3-dihydroquinazolin-4(1H)-one and benzotriazepin- 5(2H)-one derivatives, starting from the same intermediate (IIa-g). By varying the substituent on the benzamide moiety of the key intermediate (IIa-g) or the conditions of the reactions utilized in this syntheses, the reaction gives rise either quinazolin-4(1H)-one or benzotriazepine-5(2H)-one. The intermediate; 2-methylamino-N-(substituted benzoyl)benzohydrazide (IIa-g); was prepared by condensation of N-methyl-isatoic anhydride with different benzoic acid hydrazides. Constructing the intermediates (IIa-g) on different cyclo-condensation reactions; either with ethylchloroformate /potassium hydroxide or carbon disulfide/potassium hydroxide, yielded a new series of benzotriazepin-5(2H)-one (IIIa-b, IVa-d) and a new series of quinazolin4(1H)-one (Va-c, VI a-d). Pharmacological screening of the new benzotriazepinone derivatives revealed that the compounds (VI a-b, IVc-d) exhibited strong CNS depressant activity over clozapine while compounds (VIa,IVc) showed the same antipsychotic activity as clozapine with an observed neurotoxicity.

Synthesis and antimicrobial activity of newly synthesized 4-substituted-pyrazolo[3,4-d]pyrimidine derivatives

The purpose of this study was to explore the possibility of synthesizing pyrazolo[3,4-d]pyrimidine derivatives that have antimicrobial activities. A novel series of 4-substituted-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives including hydrazones (4a–i and 5), pyrazoles (6a, b) and (8), and oxadiazole-2-thiol (7), has been synthesized. Compounds 4g, 4b, 4h, 4d, 6a, 7, 8 have shown that some of the synthesized compounds have a moderate to outstanding antimicrobial activity against Gram Positive bacteria: Streptococcus pneumonia and Bacillis subtilis, gram negative bacteria: Pseudomonas aeruginosa and Escherichia coli, and fungi: Aspergillus fumigatus and Candida albicans strains. Interestingly, compound (7) “5-{[(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]methyl}-1,3,4-oxadiazole-2-thiol” exhibited superior antimicrobial activity compared to ampicillin and gentamicin suggesting that it can be used as a lead compound for further investigations.

Exploring the binding sites of Staphylococcus aureus phenylalanine tRNA synthetase: A homology model approach

Increased resistance of MRSA (multidrug resistance Staphylococcus aureus) to anti-infective drugs is a threat to global health necessitating the development of anti-infectives with novel mechanisms of action. Phenylalanine tRNA synthetase (PheRS) is a unique enzyme of the aminoacyl-tRNA synthetases (aaRSs), which are essential enzymes for protein biosynthesis. PheRS is an (αb)2 tetrameric enzyme composed of two alpha subunits (PheS) and two larger beta subunits (PheT). Our potential target in the drug development for the treatment of MRSA infections is the phenylalanine tRNA synthetase alpha subunit that contains the binding site for the natural substrate. There is no crystal structure available for S. aureus PheRS, therefore comparative structure modeling is required to establish a putative 3D structure for the required enzyme enabling development of new inhibitors with greater selectivity. The S. aureus PheRS alpha subunit homology model was constructed using Molecular Operating Environment (MOE) software. Staphylococcus haemolyticus PheRS was the main template while Thermus thermophilus PheRS was utilised to predict the enzyme binding with tRNAphe. The model has been evaluated and compared with the main template through Ramachandran plots, Verify 3D and Protein Statistical Analysis (ProSA). The query protein active site was predicted from its sequence using a conservation analysis tool. Docking suitable ligands using MOE into the constructed model were used to assess the predicted active sites. The docked ligands involved the PheRS natural substrate (phenylalanine), phenylalanyl-adenylate and several described S. aureus PheRS inhibitors.

Functionalized polymer monoliths with carbamylated amylose for the enantioselective reversed phase nano-liquid chromatographic separation of a set of racemic pharmaceuticals

Here we report the first encapsulation of three carbamylated amylose namely R-, S- and R/S-amylose 2,3(3,5-dimethylphenylcarbamate)-6-ethylphenylcarbamate in organic polymer monolith in situ capillary columns. The columns were investigated for the enantioselective nano-liquid chromatographic separation of a set of racemic pharmaceuticals, namely, α- and β-blockers, anti-inflammatory drugs, antifungal drugs, norepinephrine-dopamine reuptake inhibitors, catecholamines, sedative hypnotics, antihistaminics, anticancer drugs, and antiarrhythmic drugs. Baseline separation was achieved for several drugs under reversed phase chromatographic conditions and only few drugs were separated under normal phase conditions. The developed columns provide more economical analysis under environmentally benign conditions.

Synthesis of 125I‐lamivudine and 125I‐lamivudine‐ursodeoxycholic acid codrug

The preparation of (125) I-lamivudine ((125) I-3TC) and (125) I-lamivudine-ursodeoxycholic acid codrug ((125) I-3TC-UDCA), suitable for comparative biodistribution studies, is described. The synthesis of the unlabeled precursor 3TC-UDCA proceeds in an 11.6% yield, and the radiolabelling yields for (125) I-3TC and (125) I-3TC-UDCA were 89 and 92%, respectively. The final products are radiochemically pure (greater than 98%).

Synthesis of125I-lamivudine and125I-lamivudine-ursodeoxycholic acid codrug: Lamivudine; Ursodeoxycholic acid; Codrug/ Radioiodination; Hepatitis B

The preparation of (125) I-lamivudine ((125) I-3TC) and (125) I-lamivudine-ursodeoxycholic acid codrug ((125) I-3TC-UDCA), suitable for comparative biodistribution studies, is described. The synthesis of the unlabeled precursor 3TC-UDCA proceeds in an 11.6% yield, and the radiolabelling yields for (125) I-3TC and (125) I-3TC-UDCA were 89 and 92%, respectively. The final products are radiochemically pure (greater than 98%).