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Previously, we synthesized and evaluated several benzofuran derivatives containing heterocyclic ring substituents linked to the benzofuran nucleus at C-2 by a two- to four-atom spacer as potential anti-HIV-1, anticancer and antimicrobial agents. Among these derivatives, NSC 725612 and NSC 725716 exhibited interesting anti-HIV-1 activity. To further investigate the structure-activity relationship, we synthesized several new benzofuran derivatives derived from 2-acetylbenzofuran (2, 3a-c) and 2-bromoacetylbenzofuran (6; 7a,b; 8a,b). The compounds were designed to comprise the heterocyclic substituents directly linked to the benzofuran nucleus at C-2. Moreover, various related benzimidazoles derived from 2-acetylbenzimidazole and from 2-cyanomethylbenzimidazole (12a,b; 13a,b; 15; 16a,b) were also prepared as isosteres. The synthesized compounds were preliminarily evaluated for their in vitro anti-HIV-1, anticancer and antimicrobial activity. Compounds 2, 3a, 3b, and 12b showed weak anti-HIV-1 activity. Compound 6 exhibited mild activity against S. aureus, while compound 15 had mild activity towards S. aureus and C. albicans. However, no significant anticancer activity was observed with any of the tested compounds. From these results, we conclude that the presence of the spacer between the heterocyclic substituent and the benzofuran nucleus may be essential for the biological activity.

We have isolated an Escherichia coli gene which, when overexpressed, is able to complement the permeability defects of a vancomycin-susceptible mutant. This gene, designated sanA, is located at min 47 of the E. coli chromosome and codes for a 20-kDa protein with a highly hydrophobic amino-terminal segment. A strain carrying a null mutation of the sanA gene, transferred to the E. coli chromosome by homologous recombination, is perfectly viable, but after two generations at high temperature (43؇C), the barrier function of its envelope towards vancomycin is defective.An essential function of the outer membrane (39), an additional bilayer located outside the peptidoglycan in gram-negative bacteria such as Escherichia coli, is to act as a selective permeability barrier (38) towards hydrophobic (52) and hydrophilic compounds if the latter are larger than 600 Da (3). The outer membrane also prevents leakage of periplasmic components and controls direct passage of secreted proteins which lack classical amino-terminal signal sequences (e.g., hemolysin) from the cytoplasm to the external medium (sec-independent secretory pathway) (47). Also the outer membrane is probably responsible for the initiation of signals ultimately resulting in changes in gene expression (32).The inner leaflet of the outer membrane is composed, like the cytoplasmic membrane, of phospholipid molecules (42), whereas its outer leaflet is a unique structure composed of lipopolysaccharide (LPS) (50), porins (36), lipoproteins (14), and small amounts of enzymes (5, 26) and other minor proteins (65). The structures and biosynthetic pathways of these components are well-known, but many features of their insertion into the outer membrane and of their function are still obscure. The barrier function of the outer membrane in relation to its structure has been studied mainly by using membrane-damaging drugs (cation chelators, dyes, detergents, and local anesthetics, etc.) which modify its permeability (24, 57) and by the isolation and characterization of mutants with altered permeability towards various antibiotics (both hydrophobic and hydrophilic), dyes, and detergents (54).Gram-positive bacteria are sensitive to vancomycin, a glycopeptide antibiotic which inhibits late steps in the extracytoplasmic synthesis of cell wall peptidoglycan (44). Although hydrophilic (35), vancomycin cannot enter gram-negative bacteria because of its large size (1.4 kDa); thus, wild-type E. coli is naturally vancomycin resistant. We have undertaken the isolation, from a library of wild-type E. coli genes inserted in a bacteriophage vector, of one or several genetic determinants which can complement the defect of a recently isolated vancomycin-sensitive mutant of E. coli. Here we report the cloning, the mapping at min 47 of the E. coli chromosome, and the nucleotide sequence of a novel gene, named sanA, which when expressed from a medium-copy-number plasmid suppresses the vancomycin susceptibility as well as some other phenotypic characteristics of this mutant. The hydrophobic na...

A novel series of 1-(1-benzofuran-2-yl-ethylidene)-4-substituted thiosemicarbazides (2a-d) along with some derived ring systems: substituted-2,3-dihydro-thiazoles (3a-c, 4a-f) and thiazolidin-4-ones (5a-d and 6a-d), were synthesized. In addition, cyanoacetic acid-(1-benzofuran-2-yl-ethylidene) hydrazide (7) was used to prepare another new series of compounds consisting of substituted pyridin-2(1H)-ones (8a-c); 2-thioxo-2,3-dihydro-thiazoles (9a-d) and 2-thioxo-2,3-dihydro-6H-thiazolo[4,5-d]pyrimidin-7-ones (10a-c, 11a-c). The absolute configuration of compound 5c was determined by X-ray crystallography. The compounds prepared were evaluated for their in vitro anti-HIV, anticancer, antibacterial, and antifungal activities. Among the tested compounds, compounds 5c and 9a produced a significant reduction [symbols, see text] the viral cytopathic effect (93.19% and 59.55%) at concentrations > 2.0 x 10(-4) M and 2.5 x 10(-5) M respectively. Compound 9a was confirmed to have moderate anti-HIV activity. Compounds 2a, 2d, and 5c showed mild antifungal activity. However, none of the tested compounds showed any significant anticancer activity.

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