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This review article provides an intensive state-of-the-art over the period 2000–2022 centred around the discovery, classifications, biosynthetic pathways and therapeutic potentialities of 351 structurally diverse fungal containing-isocoumarins.

Microorganisms still remain as main hotspots in the global drug discovery avenue. In particular, fungi are highly prolific producers of a vast of structurally divers specialised secondary metabolites, which have displayed a myriad of biomedical potentialities. Intriguingly, isocoumarins is one distinctive class of fungal natural products polyketides, which demonstrated numerous remarkable biological and pharmacological activities. This review article provides a comprehensive state of the art over the period 2000-2022 about the discovery, isolation, classifications, and therapeutic potentialities of isocoumarins exclusively reported from fungi. Indeed, a comprehensive list of 351 structurally diverse isocoumarins were documented, classified according to their fungal sources [16 order/ 28 family/ 55 genera] where they have been originally discovered, alongside, their reported pharmacological activities wherever applicable. Also, recent insights around their proposed and experimentally proven biosynthetic pathways are also briefly discussed.

Lignocellulose, the structural component of plant cells, is a major agricultural byproduct and the most abundant terrestrial source of biopolymers on Earth. The complex and insoluble nature of lignocellulose limits its conversion into value-added commodities, and currently, efficient transformation requires expensive pretreatments and high loadings of enzymes. Here, we report on a fungus from the Parascedosporium genus, isolated from a wheat-straw composting community, that secretes a large and diverse array of carbohydrate-active enzymes (CAZymes) when grown on lignocellulosic substrates. We describe an oxidase activity that cleaves the major β-ether units in lignin, thereby releasing the flavonoid tricin from monocot lignin and enhancing the digestion of lignocellulose by polysaccharidase mixtures. We show that the enzyme, which holds potential for the biorefining industry, is widely distributed among lignocellulose-degrading fungi from the Sordariomycetes phylum.

In the present study, a novel series of polyfunctionalized imidazopyrimidines 6a-u and 9a-d were efficiently constructed by a domino reaction between 2-imino-6-substituted-2,3-dihydropyrimidin-4(1H)-ones 4a-d or 8a-c and 2-bromoacetophenones 5a-i under mild basic conditions. The synthesized series were screened for their antibacterial activity against Staphylococcus aureus and Bacillus subtilis as Gram-positive (+) bacteria, as well as against Gram-negative (-) bacteria Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella typhi. Most of the synthesized derivatives of imidazopyrimidines 6 and 9 showed remarkable selectivity against Gram(-) bacteria over the Gram(+) ones. Compounds 6c, 6f, and 6g displayed potent and broad-spectrum antibacterial activity against all tested strains. Compounds 6f and 6g displayed promising inhibitory activity on GryB ATPase from E. coli with IC50 = 1.14 and 0.73 μM, respectively. Simultaneously, some of the synthesized imidazopyrimidines were screened for their antiproliferative activity against 60 cancer cell lines at a concentration of 10 μM. Compound 9d showed potent activity against most of the tested cell lines, with a mean growth inhibition of 37%. The ADME (absorption, distribution, metabolism, and excretion) prediction study demonstrated that the synthesized hits have, in addition to their promising chemotherapeutic activity, acceptable pharmacokinetic properties, and a drug-likeness nature to be further developed.

Although, fluconazole is widely used in clinical treatment as an antifungal drug, it recorded potential problems as resistance and intracellular accumulation. Female albino mice were injected with single ip dose of Candida albicans (1.5 × 106 CFU). Three weeks post treatment with fluconazole and two novel synthesized compounds [(2-(4-(Pyridin-2-yl) aminosulfonylphenylamino)-6-(naphthalen-2-yl)-4-(pyridin-2-yl) pyridine-3carbonitrile) and (2-(4-(Pyrimidin-2-yl) aminosulfonylphenylamino)-6-(naphthalen-2-yl)-4-(pyridine-2-yl)pyridine-3-carbonitrile) (13b & 14b, respectively)] in both low and high doses (50 mg/kg & 200 mg/kg), liver function and vaginal inflammation were assessed. Candida albicans significantly elevated serum alanine aminotransferase (ALT) and butrylcholinesterase (BCHE) as well as hepatic malondialdehyde (MDA). Molecular analysis confirmed a significant up-regulation in mRNA gene expression of Agglutinin-like sequence (ALS1), hepatic cytochrome p450 (Cyp450). Vaginal COX-2 gene expression was also elevated. Nevertheless, a significant down-regulation was apparent in mice treated with the aforementioned compounds. Meanwhile, administration of 14b in a high dose noticeably down-regulated the altered parameters expression showing a significant effect in comparison to animals treated with the variable doses of the tested compounds. Histopathological finding confirmed the obtained results. The current work investigated the efficiency of new synthetic pyrimidine derivatives 14bas anti-microbial agents and recommended to be improved and evaluated as a novel antifungal drug to overcome the emergence of resistance problem.

An FAD-dependent monooxygenase encoding gene (SorbC) was cloned from Penicillium chrysogenum E01-10/3 and expressed as a soluble protein in Escherichia coli. The enzyme efficiently performed the oxidative dearomatisation of sorbicillin and dihydrosorbicillin to give sorbicillinol and dihydrosorbicillinol respectively. Bioinformatic examination of the gene cluster surrounding SorbC indicated the presence of two polyketide synthase (PKS) encoding genes designated sorbA and sorbB. The gene sorbA-encodes a highly reducing iterative PKS while SorbB encodes a non-reducing iterative PKS which features a reductive release domain usually involved in the production of polyketide aldehydes. Using these observations and previously reported results from isotopic feeding experiments a new and simpler biosynthetic route to the sorbicillin class of secondary metabolites is proposed which is consistent with all reported experimental results.

A new biosynthetic pathway to the sorbicillinoid natural products is proposed based on the observation of oxidative dearomatisation of dihydrosorbicillin 10b., An FAD-dependent monooxygenase encoding gene (SorbC) was cloned from Penicillium chrysogenum E01-10/3 and expressed as a soluble protein in Escherichia coli. The enzyme efficiently performed the oxidative dearomatisation of sorbicillin and dihydrosorbicillin to give sorbicillinol and dihydrosorbicillinol respectively. Bioinformatic examination of the gene cluster surrounding SorbC indicated the presence of two polyketide synthase (PKS) encoding genes designated sorbA and sorbB. The gene sorbA-encodes a highly reducing iterative PKS while SorbB encodes a non-reducing iterative PKS which features a reductive release domain usually involved in the production of polyketide aldehydes. Using these observations and previously reported results from isotopic feeding experiments a new and simpler biosynthetic route to the sorbicillin class of secondary metabolites is proposed which is consistent with all reported experimental results.