Discovery of Novel Benzoxaborole-Containing Streptochlorin Derivatives as Potential Antifungal Agents.

Streptochlorin is a kind of indole alkaloid derived from marine microorganisms. It is a promising lead compound due to its potent bioactivity in preventing many phytopathogens, as shown in our previous study. To explore the potential applications of this natural product, a series of novel benzoxaborole-containing streptochlorin derivatives were designed and synthesized through a one-step and catalyst-free reaction in water at room temperature. All target compounds were first screened for their antifungal profiles in vitro against six common phytopathogenic fungi. The results of bioassay revealed that most of the designed compounds exhibited more significant antifungal activities against Botrytis cinrea, Gibberella zeae, Rhizoctorzia solani, Colletotrichum lagenarium, and alternaria leaf spot under the concentration of 50 µg/mL, and this is highlighted by compounds 4i and 5f, which demonstrated impressive antifungal effects against G. zeae and R. solani, with their corresponding EC50 values 0.2983 and 0.2657 µg/mL, which are obviously better than positive control flutriafol and boscalid (5.2606 and 1.2048 µg/mL, respectively). Scanning electron microscopy on the hyphae morphology showed that compound 5b might cause mycelial abnormalities of G. zeae. 3D-QSAR studies of CoMFA and CoMSIA were carried out on 29 target compounds with antifungal activity against B. cinrea. The analysis results indicated that introducing appropriate electronegative groups at the 5-position of benzoxaborole and the 4,5-positions of the indole ring could effectively improve the anti-B. cinrea activity. Moreover, compound 5b showed good antifungal activities in vivo against Phytophthora capsici. Molecular docking was further explored to ascertain the practical value of the active compound as a potential inhibitor of LeuRS. The abovementioned results indicate that the designed benzoxaborole-containing streptochlorin derivatives could be further studied as template molecules of novel antifungal agents.

Design, synthesis, antifungal activity and molecular docking of ring-opened pimprinine derivative containing (thio)amide structure.

BACKGROUND: To obtain new environmentally friendly fungicides, we used the natural product pimprinine as the lead compound, and designed and synthesized two series of ring-opening derivatives of pimprinine containing amide/thioamide. We then studied their antifungal activity against six common plant pathogenic fungi in vitro. RESULTS: Most of the target compounds have good antifungal activity against six important plant pathogenic fungi in vitro. At a concentration of 50 µg ml-1 , compound 3o showed prominent antifungal effects on Alternaria solani and Rhioctornia solani, with inhibition rates of 91.8% and 97.4%, and a 50% effective concentration (EC50 ) of 6.2255 and 0.6969 µg ml-1 respectively. The EC50 of compound 3o against Alternaria solani was significantly lower than that of boscalid (13.0380 µg ml-1 ) and flutriafol (11.9057 µg ml-1 ). In addition, compound 3o had good antifungal activity against Sclerotinia sclerotiorum, cucumber powdery mildew, cucumber Botrytis cinerea and Phytophthora capsici in vivo; the antifungal activity of compound 3o against cucumber Botrytis cinerea is 91.7%. At the same time, docking results for highly active compound 3o with the presumed target succinate dehydrogenase and the molecular docking prediction scores of all compounds further indicate its possible antifungal activity mechanism. CONCLUSION: The designed and optimized derivative 3o of ring-opening pimprinine has good antifungal activity and can be used as a new antifungal drug for further research. © 2023 Society of Chemical Industry.

Design, Synthesis, Antifungal Activity, and Molecular Docking of Streptochlorin Derivatives Containing the Nitrile Group.

Based on the structures of natural products streptochlorin and pimprinine derived from marine or soil microorganisms, a series of streptochlorin derivatives containing the nitrile group were designed and synthesized through acylation and oxidative annulation. Evaluation for antifungal activity showed that compound 3a could be regarded as the most promising candidate-it demonstrated over 85% growth inhibition against Botrytis cinerea, Gibberella zeae, and Colletotrichum lagenarium, as well as a broad antifungal spectrum in primary screening at the concentration of 50 µg/mL. The SAR study revealed that non-substituent or alkyl substituent at the 2-position of oxazole ring were favorable for antifungal activity, while aryl and monosubstituted aryl were detrimental to activity. Molecular docking models indicated that 3a formed hydrogen bonds and hydrophobic interactions with Leucyl-tRNA Synthetase, offering a perspective for the possible mechanism of action for antifungal activity of the target compounds.

Discovery of Novel Pimprinine and Streptochlorin Derivatives as Potential Antifungal Agents.

Pimprinine and streptochlorin are indole alkaloids derived from marine or soil microorganisms. In our previous study, they were promising lead compounds due to their potent bioactivity in preventing many phytopathogens, but further structural modifications are required to improve their antifungal activity. In this study, pimprinine and streptochlorin were used as parent structures with the combination strategy of their structural features. Three series of target compounds were designed and synthesized. Subsequent evaluation for antifungal activity against six common phytopathogenic fungi showed that some of thee compounds possessed excellent effects, and this is highlighted by compounds 4a and 5a, displaying 99.9% growth inhibition against Gibberella zeae and Alternaria Leaf Spot under 50 µg/mL, respectively. EC50 values indicated that compounds 4a, 5a, 8c, and 8d were even more active than Azoxystrobin and Boscalid. SAR analysis revealed the relationship between 5-(3'-indolyl)oxazole scaffold and antifungal activity, which provides useful insight into the development of new target molecules. Molecular docking models indicate that compound 4a binds with leucyl-tRNA synthetase in a similar mode as AN2690, offering a perspective on the mode of action for the study of its antifungal activity. These results suggest that compounds 4a and 5a could be regarded as novel and promising antifungal agents against phytopathogens due to their valuable potency.

In Vitro Assessment of Antistaphylococci, Antitumor, Immunological and Structural Characterization of Acidic Bioactive Exopolysaccharides from Marine Bacillus cereus Isolated from Saudi Arabia.

A strain of Bacillus cereus was isolated from the Saudi Red Sea coast and identified based on culture features, biochemical characteristics, and phylogenetic analysis of 16S rRNA sequences. EPSR3 was a major fraction of exopolysaccharides (EPS) containing no sulfate and had uronic acid (28.7%). The monosaccharide composition of these fractions is composed of glucose, galacturonic acid, and arabinose with a molar ratio of 2.0: 0.8: 1.0, respectively. EPSR3 was subjected to antioxidant, antitumor, and anti-inflammatory activities. The results revealed that the whole antioxidant activity was 90.4 ± 1.6% at 1500 µg/mL after 120 min. So, the IC50 value against DPPH radical found about 500 µg/mL after 60 min. While using H2O2, the scavenging activity was 75.1 ± 1.9% at 1500 µg/mL after 60 min. The IC50 value against H2O2 radical found about 1500 µg/mL after 15 min. EPSR3 anticytotoxic effect on the proliferation of (Bladder carcinoma cell line) (T-24), (human breast carcinoma cell line) (MCF-7), and (human prostate carcinoma cell line) (PC-3) cells. The calculated IC50 for cell line T-24 was 121 ± 4.1 µg/mL, while the IC50 for cell line MCF-7 was 55.7 ± 2.3 µg/mL, and PC-3 was 61.4 ± 2.6 µg/mL. Anti-inflammatory activity was determined for EPSR3 using different methods as Lipoxygenase (LOX) inhibitory assay gave IC50 12.9 ± 1.3 µg/mL. While cyclooxygenase (COX-2) inhibitory test showed 29.6 ± 0.89 µg /mL. EPSR3 showed potent inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci. The exposure times of EPSR3 for the complete inhibition of cell viability of methicillin resistant S. aureus was found to be 5% at 60 min. Membrane stabilization inhibitory gave 35.4 ± 0.67 µg/mL. EPSR3 has antitumor activity with a reasonable margin of safety. The antitumor activity of EPSR3 may be attributed to its content from uronic acids with potential for cellular antioxidant and anticancer functional properties.

The beneficial effects of a multistrain potential probiotic, formic, and lactic acids with different vaccination regimens on broiler chickens challenged with multidrug-resistant Escherichia coli and Salmonella.

The effects of a multistrain potential probiotic (Protexin®), acids, and a bacterin from multidrug-resistant E. coli O26, O78, S. Enteritidis (1,9,12 g.m1,7), and S. Typhimurium (1,4,5,12.i.1,2) on the immune response, haematological parameters, cytokines, and growth parameters of broiler chickens challenged with bacterin live serotypes were investigated. Two experiments were designed using 300 one-day-old chicks (Arbor Acres) randomly assigned to 15 groups. The first experiment comprised 9 groups, including positive and negative control groups and other groups received Protexin®, acids, and the bacterin (0.2 ml/SC), either alone or in combination, on the 1st day. The second experiment contained 6 groups, including positive and negative control groups and other groups received a combination of Protexin®, acids, and the bacterin (0.5 ml/SC) on the 8th day. All the groups except the negative control groups were challenged on the 8th and 16th days in both experiments, respectively, with mixed live bacterin serotypes. The groups that received Protexin®, acids, and the bacterin either alone or in combination revealed significant improvements in the immune response to the bacterin (p ≤ 0.05). The groups in the 1st experiment and most the 2nd experiment groups showed a reduced mortality rate and decreased levels IFN-γ, IL-4, and IL-12 cytokines (p ≤ 0.05). Moreover, these groups demonstrated increases in haematological parameters and reduced rates of infection-caused anaemia. These groups showed significant increases in growth performance parameters, such as body weight, weight gain, and the feed conversion ratio (FCR) (p ≤ 0.05). There was a beneficial effect on 1-day-old chickens produced by combining Protexin®, acids, and the bacterin (0.2 ml/SC).

Streptochlorin analogues as potential antifungal agents: Design, synthesis, antifungal activity and molecular docking study.

Streptochlorin is a small molecule of indole alkaloid isolated from marine Streptomyces sp., it is a promising lead compound due to its potent bioactivity in preventing many phytopathogens in our previous study, but further structural modifications are required to improve its antifungal activity. Our work in this paper focused on the replacement of oxazole ring in streptochlorin with the imidazole ring, to discover novel analogues. Based on this design strategy, three series of streptochlorin analogues were efficiently synthesized through sequential Vilsmeier-Haack reaction, Van Leusen imidazole synthesis and halogenation reaction. Some of the analogues displayed excellent activity in the primary assays, and this is highlighted by compounds 4g and 4i, the growth inhibition against Alternaria Leaf Spot and Rhizoctorzia solani under 50 µg/mL are 97.5% and 90.3%, respectively, even more active than those of streptochlorin, pimprinine and Osthole. Molecular docking models indicated that streptochlorin binds with Thermus thermophiles Leucyl-tRNA Synthetase in a similar mode to AN2690, offering a perspective on the mode of action study for antifungal activities of streptochlorin derivatives. Further study is still ongoing with the aim of discovering synthetic analogues, with improved antifungal activity and clear mode of action.