amphotericin-b and 1-3-4-oxadiazole

Discovery of novel anticandidal agents with clarified mechanisms of action, could be a rationalist approach against diverse pathogenic fungal strains due to the rise of resistance to existing drugs. In support to this hypothesis, in this paper, a series of benzimidazole-oxadiazole compounds were synthesized and subjected to antifungal activity evaluation. In vitro activity assays indicated that some of the compounds exhibited moderate to potent antifungal activities against tested

Topics: Amphotericin B; Animals; Antifungal Agents; Benzimidazoles; Candida albicans; Cell Survival; Drug Design; Ketoconazole; Mice; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Structure; NIH 3T3 Cells; Oxadiazoles; Protein Binding; Structure-Activity Relationship

Fungi cause serious life-threatening infections in immunocompromised individuals and current treatments are now complicated by toxicity issues and the emergence of drug resistant strains. Consequently, there is a need for development of new antifungal drugs. Inosine monophosphate dehydrogenase (IMPDH), a key component of the de novo purine biosynthetic pathway, is essential for growth and virulence of fungi and is a potential drug target. In this study, a high-throughput screen of 114,000 drug-like compounds against Cryptococcus neoformans IMPDH was performed. We identified three 3-((5-substituted)-1,3,4-oxadiazol-2-yl)thio benzo[b]thiophene 1,1-dioxides that inhibited Cryptococcus IMPDH and also possessed whole cell antifungal activity. Analogs were synthesized to explore the SAR of these hits. Modification of the fifth substituent on the 1,3,4-oxadiazole ring yielded compounds with nanomolar in vitro activity, but with associated cytotoxicity. In contrast, two analogs generated by substituting the 1,3,4-oxadiazole ring with imidazole and 1,2,4-triazole gave reduced IMPDH inhibition in vitro, but were not cytotoxic. During enzyme kinetic studies in the presence of DTT, nucleophilic attack of a free thiol occurred with the benzo[b]thiophene 1,1-dioxide. Two representative compounds with substitution at the 5 position of the 1,3,4-oxadiazole ring, showed mixed inhibition in the absence of DTT. Incubation of these compounds with Cryptococcus IMPDH followed by mass spectrometry analysis showed non-specific and covalent binding with IMPDH at multiple cysteine residues. These results support recent reports that the benzo[b]thiophene 1,1-dioxides moiety as PAINS (pan-assay interference compounds) contributor.

Topics: Antifungal Agents; Cryptococcosis; Cryptococcus neoformans; Fungal Proteins; HEK293 Cells; Hep G2 Cells; Humans; IMP Dehydrogenase; Models, Molecular; Oxadiazoles; Thiophenes

Two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1H-tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and their structure-activity relationships are described. These compounds possessed excellent activity against Mycobacterium tuberculosis, including the clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with no cross resistance with first or second-line anti-TB drugs. The minimum inhibitory concentration (MIC) values of the most promising compounds reached 0.03 μM. Furthermore, these compounds had a highly selective antimycobacterial effect because they were completely inactive against 4 gram positive and 4 gram negative bacteria and eight fungal strains and had low in vitro toxicity for four mammalian cell lines, including hepatic cell lines HepG2 and HuH7. Although the structure-activity relationship study showed that the presence of two nitro groups is highly beneficial for antimycobacterial activity, the analogues with a trifluoromethyl group instead of one of the nitro groups maintained a high antimycobacterial activity, which indicates the possibility for further structural optimization of this class of antitubercular agents.

Topics: Antifungal Agents; Antitubercular Agents; Drug Design; Drug Resistance; Hep G2 Cells; Humans; Microbial Sensitivity Tests; Oxadiazoles; Structure-Activity Relationship; Sulfhydryl Compounds; Tetrazoles

We report synthesis and antimicrobial evaluation of 42 novel 4-nitropyrrole-based 1,3,4-oxadiazoles. The synthesized molecules were evaluated for anti-bacterial, anti-fungal and anti-tubercular activities. Promisingly, most of the compounds showed equal or more potency than standard ciprofloxacin against Staphylococcus aureus, Bacillus subtilis and Escherichia coli. Compound 5e exhibited highest anti-tubercular activity (0.46 μg/mL) close to that of standard Isoniazid (0.40 μg/mL). Equal antifungal activity (1.56 μg/mL) compared to standard Amphotericin-B was shown by most of the compounds. All the N-methylated compounds showed more potent to equal activity against MSSA (MIC 0.39-1.56 μg/mL) and MRSA (MIC 0.78-1.56 μg/mL). All compounds were tested for mammalian cell toxicity using VERO cell line and were found to be non-toxic.

Topics: Animals; Antibiotics, Antitubercular; Antifungal Agents; Bacillus subtilis; Candida albicans; Chlorocebus aethiops; Dose-Response Relationship, Drug; Escherichia coli; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Oxadiazoles; Pyrroles; Staphylococcus aureus; Structure-Activity Relationship; Vero Cells