Adaptation to Fluconazole via Aneuploidy Enables Cross-Adaptation to Amphotericin B and Flucytosine in Cryptococcus neoformans

Cryptococcosis is a globally distributed invasive fungal infection caused by infections with Cryptococcus neoformans or Cryptococcus gattii . Only three classes of therapeutic drugs are clinically available for treating cryptococcosis: polyenes (amphotericin B), azoles (fluconazole), and pyrimidine analogues (flucytosine).

Design, Synthesis and Biological Evaluation of Pyrimidine Analogues as SecA Inhibitors

SecA, a key component of the bacterial Sec-dependent secretion pathway, is an attractive target for the development of new antimicrobial agents. We have previously reported pyrimidine analogs as SecA inhibitors. Herein, we report an extension of the earlier work in the synthesis and evaluation of a series of 15 5-cyanothiouracil derivatives as SecA inhibitors. All the compounds have been evaluated for their inhibition of SecA ATPase (EcSecAN68) and for their antimicrobial activity against Escherichia coli NR698 (a leaky mutant) and Bacillus anthracis Sterne. Twelve compounds showed IC50 of less than 6.3 µM when tested against EcSecAN68. In antimicrobial studies against E. coli NR698, six compounds showed MIC of less than 12.5 µM with three being less than 6.3 µM. Against B. anthracis Sterne, three compounds showed MIC of less than 6.3 µM.

Bicyclic [1,3,4]Thiadiazolo[3,2-α]Pyrimidine Analogues: Novel One-Pot Three-Component Synthesis, Antimicrobial, and Antioxidant Evaluation

A novel one-pot three-component synthesis of 1-(7-methyl-2,5-diphenyl-5H-[1,3,4]thiadiazolo(3,2-α)pyrimidine-6-yl)ethanone (4a-i) derivatives via cyclo-condensation of substituted 2-amino-[1,3,4]thiadiazole (1a-c), acetylacetone (2) and various aromatic aldehydes (3a-c) in the presence of p-toluene sulfonic acid (PTSA) in acetonitrile. Spectral data and elemental analysis have characterized the newly synthesized compounds. The new analogs were screened for their antibacterial and antifungal activities. The majority of the tested compounds displayed significant to moderate efficacy against most of the designated organisms. Among the tested compounds, 4b, 4e, and 4h showed noteworthy efficacy against selected microbes, and compounds 4c and 4i were found to be exceptionally efficient against selected fungal strains. Compound 4c, 4e, 4f, 4i were also designated as best antioxidants against NOx.

Thiazolo-Pyrimidine Analogues: Synthesis, Characterization and Docking Studies Guided Antimicrobial Activities

In the current study, bicyclic 1-(7-methyl-3,5-diphenyl-5H-thiazolo(3,2-α)pyrimidine-6-yl)ethanone (4a-l) derivatives have been designed and conveniently synthesized by one-pot three-component method via cyclocondensation of substituted 4-phenylthiazole-2-amine (1a-c), acetylacetone (2) and various aromatic aldehydes (3a-d) in the presence of p-toluene sulfonic acid (PTSA) under acetonitrile solvent medium. The synthesized compounds (4a-l) have been characterized by spectral analysis and subjected to docking study against protein DNA gyrase (PDB Code: 1KZN), and also, the compounds were screened for their in vitro antimicrobial activities. The bioassay of the synthesized compounds envisioned that the compound 4k emerged as a broad-spectrum antibacterial agent, and 4l emerged as a good antifungal agent compared to standard drug.