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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.

Background: Amongst the quinolone core structures, 8-hydroxyquinoline (8-HQ or quinolinol) stands out as the greatest frequently used therapeutic moietiy. This includes the most critical molecules in medicinal chemistry. Quinolinol remains a broad-spectrum ligand capable of chelating to a large number of metal ions. Methods: The synthesized quinolinols Mannich bases were screened for their in vitro antimicrobial activity against Staphylococcus aureus (ATTCC 6538), Escherichia coli (ATTCC 7839), Klebsiella pneumonia (ATCC10131). The antifungal activity of the prepared compounds was assessed against Candida albicans (10231), Aspergillus niger and Penicillium sp. The antioxidant activity of the established compounds was assessed by means of α, α-diphenyl-β-picrylhydrazyl (DPPH) free radical scavenging method. Results: The antimicrobial outcomes indicated that all the synthesized compounds excluding 5 and 9b displayed reasonable antibacterial activity against Staphylococcus aureus (ATTCC 6538) and Escherichia coli (ATTCC 7839) with an inhibition zones ranging from 13 to 23 mm. However, in the case of Klebsiella pneumonia (ATCC10131) only compound 6 did not show any activity. The results also indicated that compounds 2b and 3 were the most potent antibacterial compounds against the verified strains with minimum inhibitory concentration (MIC) values ranging from 0.05 to 0.5mg/ml. In the antifungal assay, all compounds showed good activity against Candida albicans (10231) except compounds 5 and 9b. However, in the case of Aspergillus niger and Penicillium sp. only compounds 2b and 3 showed good activity. In the antifungal assay, MIC values for compounds 2b and 3 ranged from 0.25 to 2.5 mg/ml against the specified fungal strains. The antioxidant activity was assessed using the DPPH scavenging activity method. The results indicated that 2b was the most active among all tested compounds, with almost double the antioxidant activity as compared with that of trolox (positive control). Conclusion: In this work, we describe the synthesis of new Mannich bases comprising 8-HQ (1) and its derivative (8). The resulted Mannich bases of type 2 were used in transamination reactions with hydrazine and hydrazine derivatives. The structures of the newly synthesized Mannich bases were confirmed based on the NMR spectroscopic data and elemental analysis. Antimicrobial and antioxidant activities were also assessed.

The main goal of this study was to prepare and evaluate nanosponges containing ciprofloxacin (CIP) or its binary mixture with N-acetyl carnosine (NAC). Nanosponges were prepared by ultrasound-assisted synthesis technique using hydroxypropyl βeta-cyclodextrin (HPβ-CD), as the polymer and diphenyl carbonate (DPC) as the crosslinker. Entrapment efficiency (EE%) of CIP or its binary mixture with NAC in nanosponges was deduced spectrophotometrically. Nanosponges were characterized using several methods. EE% of CIP or its binary mixture with NAC inside nanosponges ranged from 98.63 ± 3.1 to 100 ± 0.07%. Particle size of nanosponges ranged from 66.7 to 90.1 nm. Release of drugs from nanosponges was biphasic and the release pattern followed Korsmeyer-Peppas model. Ex vivo and in vivo studies results showed that the antibacterial effect was enhanced with encapsulation of drugs in the nanosponge system. Furthermore, a potent antifungal activity was obtained from all examined formulae against Candida albicans (10231). The study revealed that successful encapsulation of CIP or its binary mixture with NAC in nanosponge formulations has innovated a new promising therapeutic activity for both drugs.

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.

A thermostable metallo-collagenase enzyme (150 kDa), recently identified in a newly isolated actinomycestes strain (Nocardiopsis dassonvillei NRC2aza), has been purified from natural source, characterized to have application in wound healing. A simple 3 step purification procedure gave an increase of purity by 6.23 fold with a specific activity of 387.2 U mg−1. The enzyme activity showed stability across a range of pH (7.0–8.5) and temperature (40–55 °C) with optima at pH 8.0 and 60 °C, respectively. Activators include Mg+2, Ca+2, Zn+2, Na+, K+ and Ba+2, while Mn+2, Co+2, Ni+2and Ag+ ions gave partial inhibition. Full inhibition was given by other tested ions and metalloproteinase inhibitors. Broad substrate specificity was demonstrated including activity against a native collagen. The Km and Vmax of the enzyme using azocollagen were 5.5 mg/ml and 1280 U, respectively. The purified collagenase enhanced wound closure in vitro and in vivo and the repair process was dose dependent. Topical application of the purified collagenase (either of 25 or 50 U) to cutaneous wounds significantly accelerated the rate of wound healing and the formation of granulation tissue. Hence, the purified collagenase has a great potential as a therapeutic agent in wound care and collagen related diseases.

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.

The potential application for the multiparticulate synbiotic microcapsule in yoghurt production was presented in the current study. Initially, three different formulae were fabricated to investigate the mechanism of action. This was followed by characterization the size of both of the nanoparticles and the final multiparticulate microcapsule. The yoghurt was then formed and the formulae were added and subjected to 4 weeks storage period. The viability of Bifidobacterium mixed cultures was monitored weekly. The results showed the viability of Bifidobacterium cultures was enhanced when double coated microcapsule was applied compared to the free one. The enhancement was further boosted when inulin was incorporated in either free form or in the form of nanoparticles. Scanning electron microscope image showed the final multiparticulate microcapsule has size of 700 μm while the laser diffraction particle size analyzer revealed the nanoparticles size is 118.1±4 nm. It was concluded that both of the double coat layer covering the multiparticulate microcapsule and the entrapped inulin, significantly enhanced the survivability of the encapsulated Bifidobacterium cultures in yoghurt during the shelf period.

A novel synbiotic multiparticulate microparticle was produced in the current study to expand the synbiotic industrial applications. Initially, the inulin was fabricated into PLGA nanoparticles. After the inulin entrapment efficiency was boosted to reach 92.9 ± 8.4% by adjusting the formulation parameters, the developed particles were characterized by different techniques such as particle size analyzer, TEM, and TLC. The obtained data showed that the particle size was 115.8 ± 82.7 nm, the particles had smooth surface and round shape, and the fabrication procedure did not affect the integrity of the inulin. Later, the inulin loaded nanoparticles together with selected Bifidobacterium species were double coated with gum arabic and alginate. The maximum survivability of the encapsulated Bifidobacterium in the simulated gastric solution reached 88.29% of the initial population, which was significantly higher than the survivability of the free bacteria. Finally, the inulin release from the multiparticulate microparticles was studied and found to be sustained over three days.

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.

A series of directed knockout experiments, combined with an in vitro assay of pathway components, has elucidated for the first time the chemical steps involved in the biosynthesis of the tropolone class of fungal maleic anhydrides. The pathway involves the stepwise oxidation of aldehyde and methyl carbon atoms to form a 1,2-dicarboxylate. A hydrolase-catalyzed interconversion of this and the corresponding maleic anhydride, followed by decarboxylation of the diacid leads to the pathway's final product of stipitatic acid.

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.