Diverse bioactive secondary metabolites from Aspergillus terreus: antimicrobial, anticancer, and anti-SARS-CoV-2 activity studies.

Owing to its high interest as prolific source of diverse bioactive compounds referred in our previous research work, we have scaled-up the fermentation of the marine Aspergillus terreus LGO13 on a liquid culture medium to isolate and identify the very minor/further promising bioactive secondary metabolites and to study their antibacterial, cytotoxic, and antiviral properties. Twenty-three known bioactive metabolites, including the recently discovered microbial natural product N-benzoyl-tryptophan (1), were obtained herein. Their structures were determined using HR-ESI-MS 1D/2D NMR spectroscopy and data from the literature. The biological properties of the microbial extract and the resulting compounds were examined using a set of microorganisms, cervix carcinoma KB-3-1, nonsmall cell lung cancer (NSCLC) A549, and coronavirus (SARS-CoV-2), respectively. Molecular docking (MD) simulations were used to investigate the potential targets of the separated metabolites as anti-SARS-CoV-2 drugs. According to the current study, a viral protein that may be the target of anticovid drugs is a papain-like protease (PLpro), and chaetominine (2) appears to be a viable choice against this protein. We evaluated the antiviral efficacy of chaetominine (2), fumitremorgin C (6), and azaspirofuran A (9) against SARS-CoV-2 based on MD data. Chaetominine (2) and azaspirofuran A (9) displayed intermediate selectivity indices (SI = 6.6 and 3.2, respectively), while fumitremorgin C (6) displayed a high selectivity index (SI = 19.77). These findings show that fumitremorgin C has promising antiviral action against SARS-CoV-2.

Chemical Characterization, DNA-Damage Protection, Antiproliferative Activity and in Silico Studies of the Essential Oils from Perralderia coronopifolia Coss.

In this study, for the first time, we analyzed the chemical composition of essential oils (EOs) steam-distilled from the flowers and leaves of Perralderia coronopifolia by GC-FID/MS. The objective was to explore new anticancer and antioxidant bioactive substances and understand their mechanisms of action through the use of plant-derived natural products. The major chemical components characterizing the EOs were cis-chrysanthenyl acetate 1, 6-oxocyclonerolidol 2, cis-8-acetoxychrysanthenyl acetate 3, and 6α-hydroxycyclonerolidol 4, respectively. Furthermore, the EOs inhibited cell proliferation in HeLa (human cervix carcinoma) and PC3 (human prostate cancer) cells and protected plasmid DNA from oxidative damage caused by UV-photolyzed H2 O2 . Employing a molecular docking study, we elucidated the main compounds' inhibition mechanisms. Consequently, the antitumor activity could be related to the inhibitory property of compound 3 against CDC25B phosphatase. The evaluation of ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and the density functional theory (DFT) calculations of the major compounds, especially compound 3, offer potential insights for designing and developing new cancer drug candidates. In conclusion, our study provides a framework for future research and development in the field by establishing a scientific foundation for the use of Perralderia coronopifolia essential oils as a prospective source of antioxidant and anticancer agents.

Bioactive secondary metabolites from Trichoderma viride MM21: structure elucidation, molecular docking and biological activity.

Four bioactive metabolites; ergosterol (1), peroxy ergosterol (2), α-cyclopiazonic acid (3) and kojic acid (4), were isolated from the fungal sp. Trichoderma viride MM21. Their structures were assigned by cumulative analysis of NMR and mass spectra, and comparison with literature. The antimicrobial activity of the fungus supernatant, mycelial cake, cumulative crude extract and compounds 1-4 was broadly studied against 11 diverse pathogens, revealing auspicious activity results. Based on the molecular docking, ergosterol (1) and peroxy ergosterol (2) were picked up to be computationally tested against topoisomerase IV of Staphylococcus aureus. The nominated enzyme is a possible target for the antibacterial activity of triterpenoidal/steroidal compounds. Compounds 1, 2 showed a deep inserting inside the enzyme groove recording a good binding affinity of -8.1 and -8.4 kcal/mol, respectively. Noteworthy that the antibacterial activity of ergosterol was higher (14-17 mm) than peroxy ergosterol (11-14 mm), although ergosterol formed only one hydrogen bond with the target, while peroxy ergosterol formed three hydrogen bonds. Such higher antibacterial activity of ergosterol may be attributed to its interference with other proteins included in this inhibition. The cytotoxic activity was tested against brine shrimp, revealing 100% mortality for the supernatant, crude extract and whole isolated compounds. Such strong cytotoxicity is attributed most likely to the abundant productivity/concentration of α-cyclopiazonic acid and kojic acid.

Monascin and monascinol, azaphilonoid pigments from Mortierella polycephala AM1: in silico and in vitro targeting of the angiogenic VEGFR2 kinase.

The fungus, Mortierella polycephala is one of the most productive sources of anticancer bioactive compounds namely those of pigment nature. During our investigation of the produced bioactive metabolites by the terrestrial M. polycephala AM1 isolated from Egyptian poultry feather waste, two main azaphilonoid pigments, monascin (1) and monascinol (2) were obtained as major products; their structures were identified by 1D (1H&13C) and 2D (1H-1H COSY, HMBC) NMR and HRESI-MS spectroscopic data. Biologically, cytotoxic activities of these compounds were broadly studied compared with the fungal extract. To predict the biological target for the presumed antitumor activity, an in silico study was run toward three proteins, topoisomerase IIα, topoisomerase IIß, and VEGFR2 kinase. Monascinol (2) was expected to be moderately active against VEGFR2 kinase without any anticipated inhibition toward topo II isoforms. The in vitro study confirmed the docked investigation consistently and introduced monascinol (2) rather than its counterpart (1) as a potent inhibitor to the tested VEGFR2 kinase. Taxonomically, the fungus was identified using morphological and genetic assessments.

Synthetic Analogs of Marine Alkaloid Aplysinopsin Suppress Anti-Apoptotic Protein BCL2 in Prostate Cancer.

Aplysinopsins are a class of indole alkaloids that possess various pharmacological activities. Although their action has been studied in regard to many diseases, their effect on prostate cancer has not yet been examined. Therefore, we synthesized a new series of aplysinopsin analogs and investigated their cytotoxic activity against prostate cancer. Five analogs showed high antitumor activity via suppressing the expression of the anti-apoptotic gene Bcl2, simulationously increasing the expression of the pro-apoptotic genes p53, Bax and Caspase 3. The inhibition of BCL2 led to the activation of BAX, which in turn activated Caspase 3, leading to apoptosis. This dual mechanism of action via apoptosis and cell cycle arrest induction is responsible for aplysinopsin analogs antitumor activity. Hence, our newly synthesized analogs are highly promising candidates for further preclinical studies against prostate cancer.

Collagenase and Tyrosinase Inhibitory Effect of Isolated Constituents from the Moss Polytrichum formosum.

Mosses from the genus Polytrichum have been shown to contain rare benzonaphthoxanthenones compounds, and many of these have been reported to have important biological activities. In this study, extracts from Polytrichum formosum were analyzed in vitro for their inhibitory properties on collagenase and tyrosinase activity, two important cosmetic target enzymes involved respectively in skin aging and pigmentation. The 70% ethanol extract showed a dose-dependent inhibitory effect against collagenase (IC50 = 4.65 mg/mL). The methanol extract showed a mild inhibitory effect of 44% against tyrosinase at 5.33 mg/mL. Both extracts were investigated to find the constituents having a specific affinity to the enzyme targets collagenase and tyrosinase. The known compounds ohioensin A (1), ohioensin C (3), and communin B (4), together with nor-ohioensin D (2), a new benzonaphthoxanthenone, were isolated from P. formosum. Their structures were determined by mass spectrometry and NMR spectroscopy. Compounds 1 (IC50 = 71.99 µM) and 2 (IC50 = 167.33 µM) showed inhibitory activity against collagenase. Compound 1 also exhibited inhibition of 30% against tyrosinase activity at 200 µM. The binding mode of the active compounds was theoretically generated by an in-silico approach against the 3D structures of collagenase and tyrosinase. These current results present the potential application from the moss P. formosum as a new natural source of collagenase and tyrosinase inhibitors.

New pyranosyl cembranoid diterpenes from Sarcophyton trocheliophorum.

During our continual searching programme for novel bioactive metabolites from Sarcophyton trocheliophorum, collected from Red Sea, we describe herein the isolation and structural elucidation of further two new pyrane-based cembranoid diterpenes: 9-hydroxy-7,8-dehydro-sarcotrocheliol (1) and 8,9-expoy-sarcotrocheliol acetate (2), along with the well-known sarcotrocheliol acetate (3), (+)-sarcophine (4), (+)-sarcophytoxide (5) and (-)-sarcophytoxide (6). The chemical structures of compounds 1 and 2 were determined on the basis of 1D and 2D NMR (1H, 13C, 1H-1H COSY, HMQC, HMBC and NOE), mass spectra (ESI and HR-ESIMS) and by comparison with related structures. The antimicrobial activities of the reported compounds 1-6 were investigated. According to the molecular docking study of compounds 1-6 using 3D structure of α,ß tubulin in complex with taxol (PDB code 1JFF) and epothilone A (PDB code 1TVK), sarcophine (4) displayed the highest affinity towards both crystal structures, followed by 5 and 6, meanwhile pyrane-based cembranoid diterpenes (1-3) showed less affinity.

Secondary metabolites and biological activity of Pentas species: A minireview.

The genus Pentas belongs to the Rubiaceae family, which contains approximately 40 species. Several Pentas species were reported to be used as a folk treatment by African indigenous people in treating some diseases such as malaria, tapeworms, dysentery, gonorrhea, syphilis and snake poisoning. This article covers the period from 1962 to 2017 and presents an overview of the biological activity of different Pentas species and describes their phytochemical traits. As a conclusion, the main secondary metabolites from Pentas species are quinones, highly oxygenated chromene-based structures, and iridoids. Pentas species are widely used in folk medicine but they have to be more investigated for their medicinal properties.

A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.

In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.