Raed A. Al-Qawasmeh

Synthesis and antimicrobial activity of cholic acid hydrazone analogues.

Synthesis and antimicrobial activity of cholic acid analogues 4a-t are reported. The synthesis of 4a-t was accomplished from ethylcholate 2. The hydrazone moiety was introduced via coupling of the cholic acid hydrazide (3) with appropriately functionalized aldehyde utilizing acetic acid as a catalyst. Quiet of interest in relation to the synthesized hydrazones is the formation of two rotamers s-cis.E and s-trans.E. Most compounds showed stronger antimicrobial activity against Gram-positive bacteria than Cefaclor and Cefixime. Compounds 4d, 4i and 4j indicated 15-fold stronger antimicrobial activities against Enterobacter faecalis compared to Cefaclor and Cefixime. Some of the synthesized compounds (e.g. 4a, 4c, 4d, 4i, and 4l) reflected two-folds less activity against Escherichia coli relative to Cefixime.

Post Groebke-Blackburn multicomponent protocol: synthesis of new polyfunctional imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine derivatives as potential antimicrobial agents.

New antimicrobial agents [imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine] have been synthesized. Their antimicrobial activities were conducted against various Gram-positive and Gram-negative bacteria including Staphylococcus aureus. Compounds 5d, 7a, 10a, 11a and 12a proved to efficiently inhibit the growth of all the Gram-positive and Gram-negative strains investigated. Results of this study showed that the nature of the substituents on the armed phenyl groups determined the extent of the activity of the fused imidazopyridine and/or imidazopyrimidine derivatives. Preliminary structure-activity observations revealed that groups with positive sigma and positive bi values (e.g. 5d, 6c, 12a, 12d) were significantly more active compared to other bioisosteres (e.g. 5b). Furthermore, increasing the molar refractivity of the substitution pattern (e.g. 5b, 6b and 6d) sharply decreased the antibacterial activity.

Design, Synthesis, and Qualitative Structure–Activity Evaluations of Novel β-Secretase Inhibitors as Potential Alzheimer’s Drug Leads

We have identified highly selective imidazopyridines armed with benzimidazol and/or arylimidazole as potent β-secretase inhibitors. The most effective and selective analogues demonstrated low nanomolar potency for the BACE1 enzyme as measured by FRET and cell-based (ELISA) assays and exhibited comparable affinity (KI) and high ligand efficiency (LE). In addition, these motifs were highly selective (>200) against the structurally related aspartyl protease BACE2. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported hydroxyethylene transition state inhibitor derived from isophthalic acid I. Of the most potent compounds, 34 displayed an IC50 for BACE1 of 18 nM and exhibited cellular activity with an EC50 of 37 nM in the cell-based ELISA assay, as well as high affinity (KI=17 nM) and ligand efficiency (LE=1.7 kJ/mol). Compound 34 was found to be 204-fold more selective for BACE1 compared to the closely related aspartyl protease BACE2.

A novel small molecule with potent anticancer activity inhibits cell growth by modulating intracellular labile zinc homeostasis

ML-133 is a novel small molecule with potent antiproliferative activity, as shown in cancer cell lines and in a human colon tumor xenograft model. ML-133 reduces the concentration of intracellular labile zinc in HT-29 colon cancer cells, leading to induction of the Krüppel-like factor 4 transcription factor. Krüppel-like factor 4 displaces the positive regulator SP1 from the cyclin D1 promoter, thereby negatively regulating the expression of cyclin D1 and promoting the G1-S phase arrest of cell proliferation. The antiproliferative and antitumor activity of ML-133 described in the present study suggests modulation of intracellular zinc homeostasis as a potential strategy for the treatment of several cancer types, and ML-133 represents a promising new class of antitumor agents that deserves further development. [Mol Cancer Ther 2009;8(9):2586–96]

Potent antimicrobial activity of 3-(4,5-diaryl-1H-imidazol-2-yl)-1H-indole derivatives against methicillin-resistant Staphylococcus aureus

A new series of antimicrobial derivatives [3-(4,5-diaryl-1H-imidazol-2-yl)-1H-indole)] have been synthesized with potent activity against strains of Staphylococcus aureus, including methicillin-resistant strains (MRSA). Compound 17 [3-(4,5-bis(4-fluorophenyl)-1H-imidazol-2-yl)-5-bromo-1H-indole], the most active derivative was shown to inhibit the growth of all Gram-positive strains tested, including vancomycin resistant Enterococcus faecalis and Enterococcus faecium with no activity against Gram-negative bacteria.

Differential Use of Anhydropyranosides for Enantiopure Routes to Bis-γ-butyrolactones: A New Approach to the Frameworks of Antibiotic and Anticancer Agents Isoavenaciolide and Ethisolide

Regio- and chemoselective syntheses of enantiopure bis-furanoids are described. These compounds are chirons for several families of bioactive natural products, including isoavenaciolide and ethisolide. Reaction of a 3,4-epoxy pyran with beta-ketoester dianions delivers substituted pyranosides in high yield. Cyclization then yields fused furan-pyran intermediates. Oxidation, deprotection, and rearrangement lead to bis-furanoids that bear the essential framework and stereochemistry of ethisolide and isoavenaciolide.

Tandem Multicomponent Reactions Toward the Design and Synthesis of Novel Antibacterial and Cytotoxic Motifs

The synthesis of polysubstituted imidazopyridines and imidazopyrazines through the orthogonal union of Groebke-Blackburn and Ugi reactions is described. These motifs were produced efficiently in a tandem operation without intermediate isolation. The synthesized scaffolds were biologically evaluated and found to possess potent anticancer and anti bacterial activities. Importantly, some of these motifs (e.g. compound 5) were found to possess specific anti-breast cancer activity against MCF7 cell line and others (e.g. compound 15) possess specific effects against melanoma cancer cell line (M8). Interestingly, the introduction of imidazobenzothiazole framework produced compounds with potent anti cancer activities (e.g. compounds 29 and 33) in vitro. Interestingly, many of synthesized compounds displayed potent and broad spectrum antibacterial activity against hospital-resistant clinical isolates namely, Escherichia coli, Klebsiellapneuomoniae, Staph. epidermidis, Ps. aeruginosa and Proteus vulgaris. Furthermore, many of the synthesized motifs were found to effective against Gram positive methicillin-sensitive Staphylococcus aureus (MMSA; ATCC 25923), andmethicillin-resistant Staphylococcus aureus (MRSA; ATCC 35591). These findings, however, form the foundation for further investigation in our continuing efforts to develop selective anticancer and antibacterial agents.

11-Phenyl-[b,e]-dibenzazepine compounds: novel antitumor agents.

A series of 11-phenyl-[b,e]-dibenzazepine compounds were synthesized and shown to be inhibitors of tumor cell proliferation with IC(50) values ranging from submicromolar to micromolar concentrations. Flow cytometric analyses of several active compounds demonstrated inhibition of cell cycle progression at the G(0)-G(1) phase transition resulting in G(0)-G(1) arrest.

A STEREOSPECIFIC SYNTHESIS OF TETRA-SUBSTITUTED CHIRAL PIPERAZINES

Abstract A one pot reaction of the epoxy triflates 1 or 2 with a variety of N , N ′-disubstituted ethylenediamines yields the corresponding chiral piperazine derivatives 3a-e and 4a-e of potential pharmacological interest in high yields.

A useful regioselective approach to episulfides via cis-oriented anhydro triflate sugars

An efficient method for the regioselective synthesis of episulfides, showing remarkable proteinase-inhibiting activity, from cis-oriented anhydro triflate sugars is decribed.