Bioactive γ-butyrolactones from Endophytic Fungus Aspergillus versicolor

Background and Objective: The gamma-butyrolactones is a popular class of fungal metabolites, possessing variable biological activities. In this study, the anti-microbial, anti-leishmanial, anti-malarial and cytotoxic activities of gamma-butyrolactone derivatives: Aspernolides L (1) and M (2) and butyrolactones I (3) and VI (4) separated from Aspergillus versicolor isolated from Pulicaria crispa (Asteraceae) roots were assessed. Moreover, their radioligand displacement affinity on human cannabinoid and opioid receptors was estimated. Materials and Methods: The anti-microbial effect of compounds 1-4 was assessed against Aspergillus fumigates (A. fumigates), Cryptococcus neoformans (C. neoformans), methicillin-resistant Candida albicans (C. albicans), Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli), using modified CLSI/NCCLS methods. Their anti-leishmanial capacity towards Leishmania donovani (L. donovani) as well as anti-malarial potential towards Plasmodium falciparum (P. falciparum) [(W2, Indo-China) and (D6, Sierraleon)], using plasmodial lactate dehydrogenase (pLDH) assay were evaluated. Moreover, the binding affinity towards opioid (subtypes delta, kappa and mu) and cannabinoid (CB1 and CB2) receptors were tested using in vitro radioligand displacement assay. The cytotoxic effect was evaluated towards epidermoid (KB), malignant melanoma (SK-MEL), ovarian (SK-OV-3) and ductal (BT-549) carcinomas. Results: Compounds 1 and 2 had moderate anti-microbial effect towards C albicans, A. fumigates, E. coli and P. aeruginosa with IC50 ranged from 2.60-6.04 mM. Moreover, compounds possessed anti-leishmanial potential towards L. donovani with IC50 2.31 and 3.47 mM, respectively and IC90 5.67 and 3.89 mM, respectively compared to pentamidine. While, compound 3 displayed moderate activities towards C neoformans and A. fumigates with IC50 7.90 and 9.75 mM, respectively. On the other hand, compound 2 revealed activity towards D6 and D6 S1 clones (chloroquine-sensitive strains of P. falciparum) with IC50 2.16 and 1.43 mM, respectively. Compounds 1-4 exhibited good binding affinity towards the CB1 receptor with 71.2,80.5,69.8 and 66.1%, respectively displacement values. Moreover, compound 2 showed affinity to d-, k- and m-receptors with displacement values 61.2,73.5 and 61.3%, respectively. Furthermore, compound 1 displayed cytotoxic potential towards SK-MEL with IC50 0.70 mM and 2 exhibited the highest activity towards KB, SK-MEL, BT-549 and SKOV-3 cell lines with IC50 1.2, 0.9, 0.1 and 0.8 mM, respectively. Conclusion: Compounds 1-2 could be drug leads for anti-microbial, anti-leishmanial, cytotoxic and anti-malarial agents. The good binding affinity of 1-4 towards the CB1 receptor may also provide additional information on the possible analgesic and anti-inflammatory properties of the butyrolactones which are not reported earlier.