Abdel-Nasser El-Shorbagi

New prodrug approach for amino acids and amino-acid-like drugs

Summary A series of disubstituted tetrahydro-2 H -1,3,5-thiadiazine-2-thione (THTT) derivatives 4a–g were prepared and found to be promising prodrugs for amino acids and similar compounds. The pH profile for the degradation of the THTT derivatives in aqueous buffer solutions was determined using HPLC and was accounted for in terms of specific base-catalyzed reactions. The compounds, however, showed high acid stability. Enzymatic hydrolysis (human serum) of the derivatives offered an advantageous range of t 1/2 values, which may be useful in controlling the onset and the duration of action of drugs.

New 2H-tetrahydro-1, 3, 5-thiadiazine-2-thiones incorporating glycine and glycinamide as potential antifungal agents.

The new title derivatives (4b—h and 5a—i) were synthesized by reaction of the appropriate primary amine, carbon disulphide, and formaldehyde. These derivatives were prepared in order to study the effects of introducing polar groups at N3 or N5 or at both positions on the biological activity. The compounds were tested for their antifungal activity in vitro against pathogenic (Trichophyton rubrum and Candida albicans), phytopathogenic (Penicillum expansum, Trichoderma hazianum, and Fasarium oxysporum), and aflatoxin‐producing (Aspergillus flavus) fungi. These compounds exhibited varied inhibitory effects on growth or sporulation of some tested fungal species.

New tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives as potential antimicrobial agents

The deacylated chloramphenicol amine D‐(—)‐threo‐2‐amino‐1‐(4‐nitrophenyl)‐1,3‐diol (D‐amine, 1a), and its enantiomer, the L‐(+)‐threo‐form (L‐amine, 1b), were introduced into a tetrahydro‐2H‐1,3,5‐thiadiazine‐2‐thione (THTT) skeleton. They are incorporated in three ways (Chart 1, types I‐III) at N3 (type I), N5 (type II) or both N3 and N5 (type III) of the THTT system. These selections were made in order to investigate the effect of combining the structural features of the THTT and the D‐amine on the antimicrobial activity, if any.

Flow injection method for the determination of methotrexate with a column-packed oxidizing agent

A highly sensitive flow injection technique involving oxidative cleavage and spectrofluorimetric detection was developed for the determination of methotrexate. Cerium(IV) trihydroxyhydroperoxide (CTH) was introduced as a packed reactor for the construction of a derivatization column which is used in a flowing system for conversion of methotrexate into a highly fluorescent derivative. The oxidative cleavage of methotrexate occurs during the flow of carrier stream containing the drug through the CTH column. The optimum composition of the carrier stream was found to be 0.04 mol l–1 phosphate buffer (pH 3.5). The flow rate was 0.5 ml min–1 and the column temperature was 40 °C. The fluorescent product was monitored spectrofluorimetrically at excitation and emission wavelengths of 367 and 463 nm, respectively. The proposed method was successfully applied to the determination of methotrexate in pharmaceutical preparations.

Synthesis and anti-inflammatory testing of some new compounds incorporating 5-aminosalicylic acid (5-ASA) as potential prodrugs.

This work includes the synthesis of 15 final compounds (6a-h and7b-h) as prodrugs of 5-ASA in the form of the acid itself, esters and amides linked by an amide linkage through a spacer to the endocyclic ring N of nicotinamide. Also, 15 new intermediate compounds were prepared. The target compounds (6b, 6f, 7b, and7e-h) revealed potent analgesic and anti-inflammatory activities in comparison to sulfasalazine and 5-ASA. In addition, ulcerogenicity, LD50,in vivo andin vitro metabolism of compound7f were determined.

5-Aminosalyclic Acid (5-ASA): A Unique Anti-Inflammatory Salicylate

Salicylic acid (SA) derivatives are widely used for treatment of various diseases. Acetylsalicylic acid represents the most widely used drug in the world, 4-Aminosalicylic acid (4-ASA) was historically used as a systemic antituberculosis drug as well as diflunisal is a strong pain killer and antipyretic. 5-Aminosalicylic acid (5-ASA) which had been synthesized at the end of 19th century and employed first for the production of azo dyes, was then identified as a very valuable medicinal agent as well as part of many biologically active agents. 5-ASA is not metabolized to salicylic acid for pharmacological activity. It is not considered a true salicylate. In contrary to other salicylates, 5-ASA doesn’t induce upper gastrointestinal (GI) side effects. Moreover, It was found, especially, useful for treatment of inflammatory bowel diseases (IBD). It is unique among salicylates and has a broad specrum of biological activities including, anti-inflammatory, analgesic, neuroprotective and antitumor. Since we are interested in this compound and its derivatives, we prepared this review to give insight into its chemistry, anti-inflammatory activity, in particular, for treatment of IBD. Different approaches for colonic targeting of 5-ASA w ill be covered with emphasis on chemical methods as well as its proposed mechanisms of action.

Utility of copper(II) oxide as a packed reactor in flow injection assembly for rapid analysis of some angiotensin converting enzyme inhibitors

A new simple, sensitive, rapid and precise flow injection (FI) procedure based on the formation of copper complexes with some angiotensin converting enzyme (ACE) inhibitors has been developed and evaluated for the analysis of lisinopril (LN), enalapril maleate (EP), ramipril (RP) and perindopril tert-butylamine (PD). In this method, samples were injected into a flowing stream of distilled–deionized water, carried through the packed reactor of CuO for derivatization followed by ultraviolet (UV) detection. The flow rate was 1.5 ml min−1 and column temperature was ambient (25 °C). Lisinopril was injected directly into the flowing stream and the detector response was measured at 262 nm. The hydrolysis products of enalapril maleate, ramipril and perindopril tert-butylamine in 0.2N NaOH were injected after neutralization with 1N HCl and the detector response was measured at 272, 265 and 252 nm, respectively. The developed method was successfully applied to the determination of tested drugs in pharmaceutical preparations at a sampling rate of 60 samples h−1 and a recovery near 100% for all compounds.

Kinetics of solid state stability of glycine derivatives as a model for peptides using differential scanning calorimetry

Kinetics of solid state stability of seven derivatives of 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) of glycine as a model for amino acids and peptide drugs were studied using differential scanning calorimetry (DSC). Each DSC curve for each derivative showed an endothermic peak followed by an exothermic one, which could be attributed to the melting and decomposition, respectively. The decomposition activation energy of each derivative was calculated using the Augis and Bennet, Kissinger equations and Mahadevan approximation. Also, the melting activation energies as well as the thermodynamic parameter (enthalpy) for the investigated derivatives were evaluated. The relative stability of the derivatives in the solid state according to the calculated values of the decomposition activation energy, frequency factors and half-life for each derivative could be determined.

Synthesis of cytotoxic 1-polyhydroxyalkyl-β-carboline derivatives

Summary dl -1-(1-Oxo-3,4- threo -3,4,5-trihydroxy-1-pentyl)-β-carboline 16a was synthesized from 1-formyl-β-carboline in 13 steps. The prepared compound is one of the diastereomers of an alkaloid 3 produced by the inter-generic somatic hybrid cell culture of Rauwolfia serpentina Benth and Rhazya stricta Decaisne (family: Apocynaceae). The N9-benzyl and N9-methyl derivatives 16b,c were also prepared. The final compounds and some of the intermediates showed cytotoxic activity against human promyelocytic leukemia cells HL 60 and/or human diploid embryonic lung fibroblast cells.

Design and synthesis of novel 5-aminosalicylate (5-ASA)-4-thiazolinone hybrid derivatives with promising antiproliferative activity.

Two privileged pharmacophores were assembled in one molecular frame involving 5-aminosalicylate and 4-thiazolinones that can be found in different stereochemical features. The compounds were fully characterized and evaluated for antiproliferative activity against four human cancer cell lines and some are equipotent to doxorubicin with lower cytotoxicity to normal cells. The most interesting finding relates to compound 10, which shows an IC50 value of 70nM against MCF-7 cells, while the IC50 against human fibroblasts is 10μM. The results of this study indicate that the new compounds are optimal anti-cancer leading compounds and merit further studies to optimize their structure, detect their biotargets and in vivo activity.