Biotransformation of hydroxychloroquine to evaluate the cytotoxicity of its metabolites and mimic mammalian metabolism.

Hydroxychloroquine (HCQ) displays attractive anti-inflammatory and antiviral effects. Because of that, such a drug made part of some clinical trials for combating Sars-CoV-2 during the COVID-19 pandemic. The present study aimed to conduct the biotransformation of HCQ by filamentous fungi reported as microbial models of mammalian drug metabolism to evaluate its cytotoxic after metabolization. Cunninghamella echinulata var. elegans ATCC 8688a could efficiently biotransform HCQ into one main metabolite identified as the new 4-(1,2,3,4-tetrahydroquinolin-4-ylamino)pentan-1-ol (HCQ-M). The microbial transformation occurred through N-dealkylation, 7-chloro-elimination, and reduction of the two conjugated double-bond from the quinoline system of HCQ. The cytotoxic profiles of HCQ and its metabolite were evaluated using CCD-1059Sk cells (human fibroblasts) through sulforhodamine B, trypan blue, and Live/Dead assays. Both HCQ and HCQ-M displayed cytotoxic activities in human fibroblasts, but HCQ-M was significantly more toxic than HCQ. The reported findings should be considered for further clinical studies of HCQ and will be important for guidance in achieving new derivatives from it.

Natural trypanocidal product produced by endophytic fungi through co-culturing.

Endophytic fungi live inside vegetal tissues without causing damage to the host plant and may provide lead compounds for drug discovery. The co-culture of two or more endophytic fungi can trigger silent gene clusters, which could lead to the isolation of bioactive compounds. In this study, two endophytic strains isolated from Handroanthus impetiginosus leaves, identified as Talaromyces purpurogenus H4 and Phanerochaete sp. H2, were grown in mixed and axenic cultures. The meroterpenoid austin was detected only in the extracts from the mixed culture. Once isolated, austin displayed very interesting trypanocidal activity, with an IC50 value of 36.6 ± 1.2 µg/mL against Trypanosoma cruzi in the epimastigote form. The results obtained highlight the importance of the co-culturing of endophytic fungi to obtain natural bioactive products. The findings also enhance our understanding of the ecological relationships between endophytic fungi.

Fast and Efficient Method to Obtain Tagitinin F by Photocyclization of Tagitinin C.

There is some evidence in the literature of the photocyclization reaction of Tagitinin C (1) to Tagitinin F (2). Compound 2 has high pharmacological potential, but it is not easy to obtain, while compound 1 is easily obtained from a widespread plant, Tithonia diversifolia. Among different reaction conditions monitored, one was found that allowed the cyclization of 1 into 2 in <15 min in a photo-dependent reaction. Scaling-up the photocyclization of the pure compound 1 into 2 demonstrated 100% yield, and the isolation of 2 from a UV-irradiated extract was eight-fold higher than the quantity isolated from the non-UV-irradiated extract. We were also able to better understand the process of photoconversion and determine methods to isolate and quantify these compounds, which are known for their important antitumoral activities among other important pharmacological properties.

Mapping the Biotransformation of Coumarins through Filamentous Fungi.

Natural coumarins are present in remarkable amounts as secondary metabolites in edible and medicinal plants, where they display interesting bioactivities. Considering the wide enzymatic arsenal of filamentous fungi, studies on the biotransformation of coumarins using these microorganisms have great importance in green chemical derivatization. Several reports on the biotransformation of coumarins using fungi have highlighted the achievement of chemical analogs with high selectivity by using mild and ecofriendly conditions. Prompted by the enormous pharmacological, alimentary, and chemical interest in coumarin-like compounds, this study evaluated the biotransformation of nine coumarin scaffolds using Cunninghamella elegans ATCC 10028b and Aspergillus brasiliensis ATCC 16404. The chemical reactions which were catalyzed by the microorganisms were highly selective. Among the nine studied coumarins, only two of them were biotransformed. One of the coumarins, 7-hydroxy-2,3-dihydrocyclopenta[c]chromen-4(1H)-one, was biotransformed into the new 7,9-dihydroxy-2,3-dihydrocyclopenta[c]chromen-4(1H)-one, which was generated by selective hydroxylation in an unactivated carbon. Our results highlight some chemical features of coumarin cores that are important to biotransformation using filamentous fungi.

Importance and Implications of the Production of Phenolic Secondary Metabolites by Endophytic Fungi: A Mini-Review.

In the natural products research, a valuable approach is the prospection of uncommon sources and unexplored habitat. Special attention has been given to endophytic fungi because of their ability to produce new and interesting secondary metabolites, which have several biological applications. The endophytes establish exclusive symbiotic relationships with plants and the metabolic interactions may support the synthesis of some similar valuables compounds. Among secondary metabolites, phenol-derived structures are responsible for several bioactivities such as antioxidant, cytotoxic, antimicrobial, among others. Phenolic compounds might be biosynthesized from the shikimate pathway. Although shikimic acid is a common precursor in plants, it is described as rare in microorganisms. To the best of our knowledge, this is the first review about phenolic compounds produced by endophytic fungi and a comparison has been made with those produced by the plant host. This review covers 124 phenolic secondary metabolites produced by endophytic fungi. Considering the data analyzed by us, only seven of such compounds were isolated from fungi and from their hosts. These observations claim for more attention to phenolic compounds produced by endophytic fungi with a view to understand the real importance of these compounds to endophytes survival.