Activation of Nrf2 pathway as a protective mechanism against oxidative stress-induced diseases: Potential of astaxanthin.

Astaxanthin, a red-orange liposoluble carotenoid, has been the centre of considerable attention in recent years for its numerous biological activities, notably its potent antioxidant activity. It is reported that astaxanthin elicits these biological activities via a number of cellular pathways. The Nrf2/Keap1 pathway is a major regulator of the antioxidant defence system of cells; it modulates the expression of a plethora of genes related to redox homeostasis as well as cellular detoxification. The pathway has received lots of attention as a prospective therapeutic target for diseases related to oxidative stress and inflammation. Several reports have shown that the pathway is inducible by many natural compounds. This present work reviews the Nrf2/Keap1 pathway, its regulation and involvement in diseases, provides a brief overview of naturally occurring compounds as activators of the pathway as well as discusses the effect of astaxanthin on the pathway.

Exploration of Fungicidal Activity and Mode of Action of Ferimzone Analogs.

Lead discovery and molecular target identification are important for developing novel pesticides. Scaffold hopping, an effective approach of modern medicinal and agrochemical chemistry for a rational design of target molecules, is aiming to design novel molecules with similar structures and similar/better biological performance. Herein, 24 new ferimzone derivatives were designed and synthesized by a scaffold-hopping strategy. In vitro bioassays indicated that compound 5o showed similar potency to ferimzone against Cercospora arachidicola and 2-fold higher potency than ferimzone against Alternaria solani. Compounds 5q, 6a, and 6d displayed fungicidal activity with EC50 values ranging from 1.17 to 3.84 µg/mL against Rhizoctonia solani, and compounds 5q and 6a displayed 1.6-1.8-fold higher activity than ferimzone against Fusarium graminearum. The in vivo bioassays at 200 µg/mL indicated that compound 5q was more potent than ferimzone against Pyricularia oryzae (90% vs 70% efficacy, respectively). Density functional theory (DFT) calculations elucidated the structure-energy relationship. Although the mode of action of ferimzone is still unclear, studies suggested that compound 5q significantly inhibited the growth and reproduction of R. solani, and its energy metabolism pathways (e.g., starch, sucrose, lipids, and glutathione) were seriously downregulated after a 5q treatment.

Synthesis, Fungicidal Activity and Plant Protective Properties of 1,2,3-Thiadiazole and Isothiazole-Based N-acyl-N-arylalaninates.

The addition of active groups of known fungicides, or systemic acquired resistance inducers, into novel compound molecules to search for potential antifungal compounds is a popular and effective strategy. In this work, a new series of N-acyl-N-arylalanines was developed and synthesized, in which 1,2,3-thiadiazol-5-ylcarbonyl or 3,4-dichloroisothiazol-5-ylcarbonyl (fragments from synthetic plant resistance activators tiadinil and isotianil, respectively) and a fragment of N-arylalanine, the toxophoric group of acylalanine fungicides. Several new synthesized compounds have shown moderate antifungal activity against fungi in vitro, such as B. cinerea, R. solani and S. sclerotiorum. In vivo tests against A. brassicicola showed that compound 1d was 92% effective at a concentration of 200 µg/mL, similar to level of tiadinil, a known inducer of systemic resistance. Thus, 1d could be considered a new candidate fungicide for further detailed study. The present results will advance research and influence the search for more promising fungicides for disease control in agriculture.

Enhancing astaxanthin yield in Phaffia rhodozyma: current trends and potential of phytohormones.

Astaxanthin is an important ketocarotenoid with remarkable biological activities and high economic value. In recent times, natural astaxanthin production by microorganisms has attracted much attention particularly in pharmaceuticals, nutraceuticals, cosmetics, and food and feed industries. Though, currently, productivity is still low and has restricted scale-up application in the commercial market, microbial production of astaxanthin has enormous prospects as it is a greener alternative to the predominating chemical synthesis. Over the years, Phaffia rhodozyma has attracted immense interest particularly in the field of biovalorization and sustainable production of natural nutraceuticals as a promising source of natural astaxanthin since it is able to use agro-food waste as inexpensive nutrient source. Many research works have, thus, been devoted to improving the astaxanthin yield from this yeast. Considering that the yeast was first isolated from tree exudates, the use of phytohormones and plant growth stimulators as prospective stimulants of astaxanthin production in the yeast is promising. Besides, it has been shown in several studies that phytohormones could improve cell growth and astaxanthin production of algae. Nevertheless, this option is less explored for P. rhodozyma. The few studies that have examined the effect of phytohormones on the yeast and its astaxanthin productivity reported positive results, with phytohormones such as 6-benzylaminopurin and gibberellic acid resulting in increased expression of carotenogenesis genes. Although the evidence available is scanty, the results are promising. KEY POINTS: • Phaffia rhodozyma is a promising source of natural astaxanthin • For industrialization, astaxanthin productivity of P. rhodozyma still needs optimization • Phytohormones could potentially augment astaxanthin yield of P. rhodozyma.

Natural antioxidants in diabetes treatment and management: prospects of astaxanthin.

Diabetes remains a major health emergency in our entire world, affecting hundreds of millions of people worldwide. In conjunction with its much-dreaded complications (e.g., nephropathy, neuropathy, retinopathy, cardiovascular diseases, etc.) it substantially reduces the quality of life, increases mortality as well as economic burden among patients. Over the years, oxidative stress and inflammation have been highlighted as key players in the development and progression of diabetes and its associated complications. Much research has been devoted, as such, to the role of antioxidants in diabetes. Astaxanthin is a powerful antioxidant found mostly in marine organisms. Over the past years, several studies have demonstrated that astaxanthin could be useful in the treatment and management of diabetes. It has been shown to protect ß-cells, neurons as well as several organs including the eyes, kidney, liver, etc. against oxidative injuries experienced during diabetes. Furthermore, it improves glucose and lipid metabolism along with cardiovascular health. Its beneficial effects are exerted through multiple actions on cellular functions. Considering these and the fact that foods and natural products with biological and pharmacological activities are of much interest in the 21st-century food and drug industry, astaxanthin has a bright prospect in the management of diabetes and its complications.

Synthesis of novel N-(2-phenyl-3-pyridyl) thiadiazole/isothiazole carboxamide analogs as potent plant elicitors.

BACKGROUND: Plant elicitors are a class of plant protection agents that can stimulate plant immunity against phytopathogen without a potential resistance problem. In searching for novel plant elicitor candidates, a series of novel N-(2-phenyl-3-pyridyl) thiadiazole/isothiazole carboxamide analogs were designed and synthesized. RESULTS: In vitro bioassay showed that all new compounds exhibited weak direct fungicidal activity. However, compounds 3b, 3g, 3n and 3o showed broad spectrum of in vivo activity against four plant fungi tested. In particularly, 3g showed 80% activity against Rhizoctonia solani in a glasshouse at a concentration of 1 µg mL-1 . For induction activity of tobacco against tobacco mosaic virus (TMV), compounds 3c and 3v showed 67% and 68% inhibitory activity, respectively, which were superior to the positive controls ribavirin and ningnanmycin. Compound 3g showed moderate induction activity (41%). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis found that, 3g could up-regulate expression of genes that are related to reactive oxygen species (ROS), pathogenesis-related protein (PRP) and salicylic acid (SA) signalling. CONCLUSION: These results indicated that 3g as an elicitor candidate might act on the SA signalling pathway. According to our findings, N-(2-phenyl-3-pyridyl) thiadiazole/isothiazole carboxamide analogs might be promising lead scaffolds as a novel plant elicitor for further investigation.

Synthesis, Fungicidal Activity, and Molecular Docking of 2-Acylamino and 2-Thioacylamino Derivatives of 1H-benzo[d]imidazoles as Anti-Tubulin Agents.

This work deals with the synthesis and evaluation of fungicidal activity of benzimidazole derivatives, which are structural analogues of commercial anti-tubulin fungicides. A number of N-acyl and N-thioacyl derivatives of 2-amino-1H-benzo[d]imidazole were prepared, and their fungicidal activity against 13 strains of phytopathogenic fungi was studied. The most active compounds against the majority of the studied strains were 3a, 4l, and 4o, and the EC50 values of these compounds were in the range 2.5-20 µg/mL. Compound 3a showed the highest activity against the P. infestans strain, the growth of which is not suppressed by carbendazim. The formation of ligand-receptor complexes of various tautomeric forms of the studied benzimidazoles with homologous models of ß-tubulins of B. cinerea, F. oxysporum, and P. infestans was modeled. Induced fit docking has been used for the simulation. The obtained data suggest the possibility of binding of benzimidazole fungicides to ß-tubulin in the ″nocodazole cavity″ in the tautomeric form bearing a double exocyclic C═N bond. The importance of the formation of hydrogen bonds of benzimidazoles with the amino acid residue Val236 along with the Glu198 residue is also revealed in the present study.

Discovery of Novel 3,4-Dichloroisothiazole-Containing Coumarins as Fungicidal Leads.

Natural products are one of the resources for discovering novel fungicidal leads. As a natural fungicide, osthole was used as a coumarin-based lead compound for the development of novel fungicides. Here, a series of 3,4-dichloroisothiazole-containing 7-hydroxycoumarins were rationally designed, synthesized, and characterized by introducing a bioactive substructure, 3,4-dichloroisothiazole, into the coumarin skeleton. In vitro bioassay indicated that compound 7g displayed good activity against Rhizoctonia solani, Physalospora piricola, Sclerotinia sclerotiorum, and Botrytis cinerea. Its median effective concentration (EC50) value against each of these fungi fell between 0.88 and 2.50 µg/mL, which was much lower than that of osthole against the corresponding pathogen (between 7.38 and 74.59 µg/mL). In vivo screening validated that 7k exhibited 100%, 60%, and 20% efficacy against R. solani Kühn at 200, 100, and 50 µg/mL, respectively. RNA sequence analysis implied that growth inhibition of R. solani by 7k might result from potential disruptions of fungal membrane formation and intracellular metabolism. Furthermore, a field experiment with cucumber plants indicated that 7b showed 62.73% and 74.03% efficacy against Pseudoperonospora cubensis (Berk. & Curt.) Rostov. at rates of 12.5 g a.i./ha and 25 g a.i./ha, respectively, which showed no significant difference between 7b and osthole at 30 g a.i./ha. Our studies suggested that 7b, 7g, and 7k might be used as fungicidal leads for further optimization.

Design, synthesis and antifungal activity of (E)-3-acyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one analogues.

Nitrogen- or oxygen-containing organic compounds which have significant antifungal activity, twenty one novel nitrogen or oxygen-containing (E)-3-acyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one analogues were designed and synthesized, and their structures were confirmed by 1H NMR, 13C NMR and HRMS. Preliminary bioassay showed that most of them exhibited certain-to-good antifungal activity. Compounds 5k-2, 5n, 5p and 5r exhibited over 80% inhibitory rate against Sclerotinia sclerotiorum at 50 µg/mL, and 5r exhibited good antifungal activity against S. sclerotiorum with EC50 of 7.21 µg/mL. Compounds 5a and 5r also showed over 90% inhibition against Botrytis cinerea. In particular, 5r showed significant higher activity with the lowest EC50 of 7.92 µg/mL than the positive control trifloxystrobin (21.96 µg/mL) and azoxystrobin (9.43 µg/mL). Providing a practical method for the synthesis of new scaffolds 1,2-Benzoxazepinone and systematically investigate their antifungal activity.

Synthesis and Biological Activity of Novel Succinate Dehydrogenase Inhibitor Derivatives as Potent Fungicide Candidates.

In searching for novel fungicidal leads, the novel bioactive succinate dehydrogenase inhibitor (SDHI) derivatives were designed and synthesized by the inversion of carbonyl and amide groups. Bioassay indicated that compound 5i stood out with a broad spectrum of in vitro activity against five fungi. Its EC50 value (0.73 µg/mL) was comparable to that of boscalid (EC50 of 0.51 µg/mL) and fluxapyroxad (EC50 of 0.19 µg/mL) against Sclerotinia sclerotiorum. For Rhizoctonia cerealis, 5i and 5p with EC50 values of 4.61 and 6.48 µg/mL, respectively, showed significantly higher activity than fluxapyroxad with the EC50 value of 16.99 µg/mL. In vivo fungicidal activity of 5i exhibited an excellent inhibitory rate (100%) against Puccinia sorghi at 50 µg/mL, while the positive control boscalid showed only a 70% inhibitory rate. Moreover, 5i showed promising fungicidal activity with a 60% inhibitory rate against Rhizoctonia solani at 1 µg/mL, which was better than that of boscalid (30%). Compound 5i possessed better in vivo efficacy against P. sorghi and R. solani than boscalid. Molecular docking showed that even the carbonyl oxygen atom of 5i was far from the pyrazole ring. It could also form hydrogen bonds toward the hydroxyl hydrogen and amino hydrogen of TYR58 and TRP173 on SDH, respectively, which consisted of the positive control fluxapyroxad. Fluorescence quenching analysis and SDH enzymatic inhibition studies also validated its mode of action. Our studies showed that 5i was worthy of further investigation as a promising fungicide candidate.

Discovery of Methyl (5 Z)-[2-(2,4,5-Trioxopyrrolidin-3-ylidene)-4-oxo-1,3-thiazolidin-5-ylidene]acetates as Antifungal Agents against Potato Diseases.

Synthesis, isomerism, and fungicidal activity against potato diseases of new (5 Z)-[2-(2,4,5-trioxopyrrolidin-3-ylidene)-4-oxo-1,3-thiazolidin-5-ylidene]acetate derivatives with 1,3-thiazolidine-4-one and pyrrolidine-2,3,5-trione moieties linked by an exocyclic C═C bond were described. Their structures were clearly confirmed by spectroscopic and spectrometric data (Fourier transform infrared spectroscopy, 1H and 13C nuclear magnetic resonance, and mass spectrometry), elemental analysis, and X-ray diffraction crystallography. A bioassay for antifungal activity in vitro against Phytophthora infestans, Fusariun solani, Alternaria solani, Rhizoctonia solani, and Colletotrichum coccodes demonstrated that 2,4,5-trioxopyrrolidin-1,3-thiazolidine derivatives exhibited a relatively broad spectrum of antifungal activity. One of the compounds showed considerable activity against all of the strains; in the case of F. solani, P. infestans, and A. solani, it possesses comparable or better fungicidal efficacy than the positive control Consento. Consequently, this compound is a promising fungicidal candidate for plant protection.

Crystal structure of 1-meth-oxy-5-methyl-N-phenyl-1,2,3-triazole-4-carboxamide.

The title compound, C 11H12N4O2,was prepared via the transformation of sodium 4-acetyl-1-phenyl-1H-[1.2.3]triazolate under the action of meth-oxy-amine hydro-chloride. The dihedral angle between the triazole and phenyl rings is 25.12 (16)° and the C atom of the meth-oxy group deviates from the triazole plane by 0.894 (4)Å. The conformation of the CONHR-group is consolodated by an intra-molecular N-H⋯N hydrogen bond to an N-atom of the triazole ring, which closes an S(5) ring. In the crystal, weak N-H⋯N hydrogen bonds link the mol-ecules into C(6) [010] chains.

The tert-amino effect in heterocyclic chemistry. Synthesis of spiro heterocycles.

The tert-amino reaction effect was examined. A new method to synthesize spiro heterocycles is presented. It was shown that the "tert-amino effect" could be applied to the formation of spiro-fused heterocycles. The formation of spiro compounds proceeds in most cases in good yields in a one-pot reaction.