benzofurans and Candidiasis

We have synthesized various amide derivatives of benzodifuran-2-carboxylic acid from resorcinol. Reaction of 7-hydroxy-4-methylcoumarin with chloroacetone in anhydrous K2CO3 and dry acetone gave ether derivative of 7-hydroxy-4-methylcoumarin 3 which on reaction with N-bromosuccinimide in chloroform gave corresponding 3-bromo derivative 4. Cyclization of bromo derivative in 10% ethanolic KOH gave benzodifuran-2-carboxylic acid 5. This acid was converted into acid chloride using oxalyl chloride and then substituted with different amines in presence of base, triethylamine to give amide derivatives of benzodifuran-2-carboxylic acid 6. All compounds were screened for antimicrobial activity against two Gram positive bacteria Staphylococus aureus and Bacillus subtilis, two Gram negative bacteria E. coli and P. aeruginosa and one fungus Candida albicans.

Topics: Amides; Anti-Infective Agents; Bacterial Infections; Benzofurans; Candida albicans; Candidiasis; Carboxylic Acids; Cyclization; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Microbial Sensitivity Tests

The activity of usnic acid against Candida orthopsilosis and Candida parapsilosis on planktonic and biofilm conditions was investigated by using a broth microdilution and microplate methods. Potent in vitro activities against different Candida species were obtained. The metabolic activity of sessile cells of C. parapsilosis complex was reduced by 80% at four times the 80% inhibitory concentration. The in vitro studies support further efforts to determine whether usnic acid can be used clinically to cure patients with Candida infections.

Topics: Antifungal Agents; Benzofurans; Biofilms; Candida; Candidiasis; Humans; Microbial Sensitivity Tests; Plankton

Thirteen compounds, based on benzofuran skeleton bearing aryl substituents at its C-3 position through methanone linker, were synthesized and screened for their antibacterial and antifungal activities against four bacteria Escherichia coli, Staphylococcus aureus, Methicillin-resistant S.aureus, Bacillus subtilis, and a fungus Candida albicans. Four hydrophobic benzofuran analogs were found to exhibit favorable antibacterial activities (MIC(80) = 0.39-3.12 μg/mL), which were better than the control drugs.

Topics: Anti-Bacterial Agents; Antifungal Agents; Bacillus subtilis; Bacterial Infections; Benzofurans; Candida albicans; Candidiasis; Cell Proliferation; Escherichia coli; Humans; Hydrophobic and Hydrophilic Interactions; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcus aureus; Structure-Activity Relationship

The C-4 side chain modification of lead compound 1 has resulted in the identification of a potent and selective Candida albicans N-myristoyltransferase (CaNmt) inhibitor RO-09-4609, which exhibits antifungal activity against C. albicans in vitro. Further modification of its C-2 substituent has led to the discovery of RO-09-4879, which exhibits antifungal activity in vivo. The drug design is based on X-ray crystal analysis of a CaNmt complex with benzofuran derivative 4a. The optimization incorporates various biological investigations including a quasi in vivo assay and pharmacokinetic study. The computer aided drug design, synthesis, structure-activity relationships, and biological properties of RO-09-4879 are described in detail.

Topics: Acyltransferases; Animals; Antifungal Agents; Benzofurans; Candida albicans; Candidiasis; Drug Design; Drug Resistance, Fungal; Enzyme Inhibitors; Fungal Proteins; Inhibitory Concentration 50; Male; Protein Binding; Rats; Rats, Inbred F344; Structure-Activity Relationship

Modification of the C-2 position of a benzofuran derivative 6 (RO-09-4609), an N-myristoyltransferase (Nmt) inhibitor, has led us to discover antifungal agents that are active in a murine systemic candidiasis model. The drug design is based on the analysis of a crystal structure of a Candida Nmt complex with 2. The optimization has been guided by various biological evaluations including a quasi in vivo assay and pharmacokinetic analysis.

Topics: Acyltransferases; Animals; Antifungal Agents; Area Under Curve; Benzofurans; Candida albicans; Candidiasis; Crystallography, X-Ray; Disease Models, Animal; Drug Design; Humans; Mice; Protein Binding; Rats; Rats, Inbred F344; Structure-Activity Relationship

A series of halogen-substituted isobenzofuran analogues was synthesized, which represented conformationally constrained analogues of miconazole (1). In vitro and in vivo topical antifungal activity against both dermatophytes and Candida species varied widely, but 13c proved to be significantly superior to both 1 and clotrimazole against a vaginal Candida infection in hamsters, while 13b was significantly more active than 1 against a a topical Trichophyton infection in guinea pigs. None of the compounds were orally active. When the most direct analogue of 1 proved to be among the least active, a molecular modeling study was done using 1, the two active analogues 13b and 13c, and the inactive analogue 13a. All four compounds possessed skeletally similar conformations either at or energetically readily accessible from the global minimum energy conformations. This common conformation of the inactive analogue 13a, however, occupies unique molecular volume space associated with two chlorine atoms, which must also present unique electrostatic properties at the receptor. The conformation-activity relationships discussed may contribute toward deduction of additional structural requirements for pharmacophore optimization and more efficacious antifungal drugs.

Topics: Animals; Antifungal Agents; Benzofurans; Candidiasis; Computer Simulation; Cricetinae; Female; Guinea Pigs; Mice; Miconazole; Microbial Sensitivity Tests; Models, Molecular; Molecular Conformation; Structure-Activity Relationship; Tinea