Specific brain delivery of pyridyl chloroethylurea derivatives as potential antitumor agents: synthesis, evaluation and molecular modeling study

The present investigation describes the synthesis; evaluation and molecular modeling studies of a series of 1-substituted-1, 4-dihydropyridine-3-chloroethylurea derivatives IIIa-e as potential agents for treatment of brain tumors. The incorporation of the 1, 4-dihydropyridine moiety in the structure attains an efficient site specific chemical delivery system [CDS] of the chloroethylurea [CEU] as a known antitumor pharmacophore to the brain. The target compounds IIIa-e were synthesized through reduction of the corresponding quaternary compounds IIa-e. The in-vitro oxidation studies showed that, compounds IIIa-e could be oxidized into their corresponding quaternary compounds II-a-e, respectively which attains their "locked in" characteristics as brain antitumor agents. The in-vivo studies showed that compound IIIa was able to cross the BBB at detectable concentration. In addition the in-vitro alkylating activity studies using 4-[4-nitrobenzyl] pyridine [NBP] revealed that compound IIe is an efficient alkylating agent with activity comparable to reference thug chlorambucil. The target compounds were tested for their binding to the colchicine-binding site [CBS] of beta-tubulin using Molecular Operating Environment [MOE] software

Analysis of paracetaiiviol and ascorbic acid in pharmaceutical binary mixture

Two simple and sensitive spectrophotometric methods were developed for the determinagion of paracetamol [I] and ascorbic acid [II] in pharmaceutical binary mixture. The first method depends on the use of the first-derivative spectrophotometric technique for the slinultaneons determination of components of the mixture. The second method depends on the reaction of the studied drugs with 5-diazo-1, 2, 4-triazol-3-carboxylic acid [DTCA] reagent to give colored products measured at 480 nm and 580 nm for [I] and [II] respectively. All variables affecting reaction conditions were optimized The proposed methods were successfully applied for the analysis of the studied drugs in their pare and commercial dosage forms and are in good agreement with those obtained from the reported methods. No significant difference in the acuracy and precision as revealed by the accepted values of t- and F-tests, respectively. Molar ratios of the drugs with the colorimetric reagent [DTCA] were determined and the reaction mechanisms were suggested

Design, synthesis and molecular modeling study of 1,2,4-triazole carbohydrazide derivatives with potential antimicrobial and anti-inflammatory activities

The present investigation is concerned with the synthesis of 1,2,4-triazole carbohydrazide derivatives [6a-I] with the objective of discovering novel and potent antimicrobial and anti-inflammatory agents. The chemical structures of the target compounds were elucidated by elemental analyses, IR, [1]H-NMR, [13]C-NMR and mass spectral data. The antimicrobial activity of the target compounds were evaluated and compared with ampicillin trihydrate and clotrimazole as references compounds. The results showed that compound 6i revealed a similiar level of activity as ampicillin against Staphylococcus aureus, while compounds 6j and 6l exhibited comparable activity against Escherichia coli. All compounds were less active against Candida albicans when compared with clotrimazole. The results of anti-inflammatory showed that compounds 6d, 6l possessed higher anti-inflammatory activity than celecoxib in carageenan-induced rat paw edema test with low gastric ulcerogenicity compared with indomethacin. Molecular modeling studies were performed in order to rationalize the obtained biological results

Synthesis of 2-trifluoromethyl-4, 7-dihydro-7-oxo -[l,2,4]triazolo[1,5-a] pyrimidine-6-carboxylic acid derivatives as potential antimyco-bacterial and antimicrobial Agents

Syntheses of the target compounds were achieved by reaction of 3-amino-5-trifluoromethyl-l, 2, 4-triazole 1 and diethylethoxymethylenemalonate [DEEA] in glacial acetic acid to afford ethyl 2-[trifluoromethyl]-4, 7-dihydro-7-oxo[l, 2, 4]-triazolo [1, 5-a]pyrimidine-6-carboxylate 2. Reaction of compound 2 with hydroxylamine hydrochloride gave hydroxamic acid 3, while reaction with hydrazine hydrate in methanol gave the corresponding carbohydrazide 4. Schiff bases of compound 4 with appropriate aldehyde yielded series 5a-g. Refluxing of hydrazide 4 with appropriate isothiocyanate gave thiosemicarbazides 6a-f. The antimycobacterial evaluation was determined against Mycobacterium tuberculosis H[37]Rv [ATCC 27294]. Compound 5e and 5b showed activity with IC90 [6. 672, 7, 362 micro g/ml respectively] and IC50 [4.627, 6.382 micro g/ml respectively]. In vitro antibacterial screening for the prepared compounds were determined against certain strains of gram positive and gram negative bacteria. The results showed that compounds 3, 5a, 6b possessed higher activity than ampicillin against all strains, also the activity range from half to sixth activity of nalidixic acid against E. coli. Compounds 3, 5a, 5b, 5c, 5f, 6b exhibited activity against P. aeruginosa, while nalidixic acid possessed no activity. Compounds 3, 5a, 5b and 6b possessed antifungal activity

Novel 1,2,4-triazole-3-mercaptoacetic acid derivatives as potential anti-mycobacterial and antimicrobial agents

Novel Schiff bases of 4-methyl 1,2,4-triazole-3-mercaptoacetic acid hydrazide were synthesized. Their chemical identities were elucidated by elemental analyses, IR, [1] H-NMR, [13] C-NMR and mass spectral data. The percentage of the geometrical isomers was also elucidated using the [1] H-NMR. The synthesized compounds were selected for screening at the Tuberculosis Antimicrobial Acquisition and Coordination Facility [TAACF] against Mycobacterium tuberculosis H [37] R [v] strain in which they showed moderate activity at a concentration of 6.25 micro g/ml. Moreover, antimicrobial screenings against E. coli [ATCC 25922], S. aureus [ATCC 19433] and C. albicans identified compound 4g as the most effective showing similar antibacterial activity as ampicillin against S. aureus

Allophenylnorstatine-containing HIV-1 protease inhibitors: design, synthesis and structure-activity relationships for selected P

The design and development of potent HIV protease inhibitors remain an attractive target for antiviral therapy. A novel class of HIV protease inhibitors containing allophenylnorstatine [Apns; [2S,3S]-3-amino-2-hydroxy-4-phenylbutyric acid] as a transition state mimic have been reported. In this work we fixed P 2' [as tert-butylamino or 2-methylbenzylamino] and changed P 2 moiety to provide two series of dipeptide analogs. Preliminary evaluation of the activity of the synthesized derivatives were determined as percentage of enzyme inhibition at 5 microM level. The results showed that the introduction of 2-methylbenzylamino moiety as P 2' ligand 6a-e considerably improved HIV inhibitory activity in comparison with the tert-butyl amino analogs 5a-e. It was found that compounds in both series retained activity still less than the lead compounds KNI-577 and KNI-727