Synthesis, antifungal evaluation, two-dimensional quantitative structure-activity relationship and molecular docking studies of isoxazole derivatives as potential fungicides.

BACKGROUND: Sheath blight and bakanae disease, prominent among emerging rice ailments, exert a profound impact on rice productivity, causing severe impediments to crop yield. Excessive use of older fungicides may lead to the development of resistance in the pathogen. Indeed, a pressing and immediate need exists for novel, low-toxicity and highly selective fungicides that can effectively combat resistant fungal strains. RESULTS: A series of 20 isoxazole derivatives were synthesized using alkoxy/halo acetophenones and N,N-dimethylformamidedimethylacetal. These compounds were characterized by various spectroscopic techniques, namely 1H nuclear magnetic resonance (NMR), 13C NMR and liquid chromatography-high-resolution mass spectrometry, and were evaluated for their fungicidal activity against Rhizoctonia solani and Fusarium fujikuroi. Compound 5n (5-(2-chlorophenyl) isoxazole) exhibited highest activity (effective dose for 50% inhibition [ED50] = 4.43 µg mL-1) against R. solani, while 5p (5-(2,4-dichloro-2-hydroxylphenyl) isoxazole) exhibited highest activity (ED50 = 6.7 µg mL-1) against F. fujikuroi. Two-dimensional quantitative structural-activity relationship (QSAR) analysis, particularly multiple linear regression (MLR) (Model 1), highlighted chi6chain and DistTopo as the key descriptors influencing fungicidal activity. Molecular docking studies revealed the potential of these isoxazole derivatives as novel fungicides targeting sterol 14α-demethylase enzyme, suggesting their importance as crucial intermediates for the development of novel and effective fungicides. CONCLUSION: All test compounds were effective in inhibiting both fungi, according to the QSAR model, with various descriptors, such as structural, molecular shape analysis, electronic and thermodynamic, playing an important role. Molecular docking studies confirmed that these compounds can potentially replace commercially available fungicides and help control fungal pathogens in rice crops effectively. © 2024 Society of Chemical Industry.

Green synthesis, structure-activity relationships, in silico molecular docking, and antifungal activities of novel prenylated chalcones.

A series of 16 novel prenylated chalcones (5A-5P) was synthesized by microwave-assisted green synthesis using 5-prenyloxy-2-hydroxyacetophenone and different benzaldehydes. Comparisons were also performed between the microwave and conventional methods in terms of the reaction times and yields of all compounds, where the reaction times in the microwave and conventional methods were 1-4 min and 12-48 h, respectively. The synthesized compounds were characterized using different spectroscopic techniques, including IR, 1H-NMR, 13C-NMR, and LC-HRMS. The antifungal activities of all compounds were evaluated against Sclerotium rolfsii and Fusarium oxysporum under in vitro conditions and were additionally supported by structure-activity relationship (SAR) and molecular docking studies. Out of the 16 compounds screened, 2'-hydroxy-4-benzyloxy-5'-O-prenylchalcone (5P) showed the highest activity against both S. rolfsii and F. oxysporum, with ED50 of 25.02 and 31.87 mg/L, respectively. The molecular docking studies of the prenylated chalcones within the active sites of the EF1α and RPB2 gene sequences and FoCut5a sequence as the respective receptors for S. rolfsii and F. oxysporum revealed the importance of the compounds, where the binding energies of the docked molecules ranged from -38.3538 to -26.6837 kcal/mol for S. rolfsii and -43.400 to -23.839 kcal/mol for F. oxysporum. Additional docking parameters showed that these compounds formed stable complexes with the protein molecules.

Synthesis of benzothiazole-appended bis-triazole-based structural isomers with promising antifungal activity against Rhizoctonia solani.

In order to explore new antifungal agrochemicals, we reported the synthesis of two series 5a-f, 6 and 7a-f, 8 of benzothiazole-appended bis-triazole derivative-based structural isomers using a molecular hybridization approach. The synthesized compounds were tested for fungal growth inhibition against the plant pathogen Rhizoctonia solani. All the synthesized compounds showed excellent antifungal activity in their minimum concentrations (10-0.62 µM). Among all the synthetics, compounds 5b (ED50: 2.33 µM), 5f (ED50: 0.96 µM), and 7f (ED50: 1.48 µM) exerted a superior inhibitory effect in comparison to the commercially available fungicide, hexaconazole (ED50: 2.44 µM). The binding interactions of the active compounds 5f, 7f, 6, and 8 within the active site of the sterol 14α-demethylase enzyme were studied with the help of molecular docking studies. The studies revealed that these hybrid pharmacophores could be used as an important intermediate to demonstrate new structural isomer-based fungicides.

Bioefficacy evaluation of ferrocenyl chalcones against Meloidogyne incognita and Sclerotium rolfsii infestation in tomato.

The present study reports, bioefficacy evaluation of effective compounds against Meloidogyne incognita and Sclerotium rolfsii in pot cultured tomato. The identified five most effective compounds, i.e. (2E)-1-(4-Methylphenyl)-3-ferrocenyl-prop-2-en-1-one (6g), (2E)-1-(4-Methoxyphenyl)-3-ferrocenyl-prop-2-en-1-one (6h), (2E)-1-(3-Bromophenyl)-3-ferrocenyl-prop-2-en-1-one (6j), (2E)-1-(2,4-Dichlorophenyl)-3-ferrocenyl-prop-2-en-1-one (6k) and (2E)-1-(3,5-Dichloro-2-hydroxyphenyl)-3-ferrocenyl-prop-2-en-1-one (6p) along with Carbofuran 3G as positive control were tested at 20, 40 and 80 ppm by soil drenching and root dipping methods. The study revealed that all plant growth parameters were positively influenced by these compounds. The presence of an electron releasing group positively influenced the efficacy, and the activity was highest in compounds 6g and 6h at 80 ppm. Based on in vitro results against S. rolfsii, (2E)-1-Ferrocenyl-3-(4-bromophenyl)-prop-2-en-1-one (3b), (2E)-1-Ferrocenyl-3-(2,6-dichlorophenyl)-prop-2-en-1-one (3o) and (2E)-1-(5-Chloro-2-hydroxyphenyl)-3-ferrocenyl-prop-2-en-1-one (6o) along with Tebuconazole 25.9% EC and Hexaconazole 5% SC as positive control were evaluated. The shoot length was found to be highest (24.50 cm) in plants treated with 3b followed by 3o and 6o at 1000 ppm. The percent disease incidence was significantly decreased as compared to control. The percent disease incidence was found to be minimum in plants treated with 3b at 1000 ppm. However, root dipping was not as effective as soil drenching. Therefore, ferrocenyl chalcone derivatives proved to be of great fungicidal and nematicidal potential opening new opportunities for expanding their effectiveness as new pest control agents.

Bioefficacy evaluation of chalcone derivatives against Meloidogyne graminicola infecting rice, Oryza sativa L.

A series of chalcones (1-14) were synthesized, characterized (using IR and 1H NMR techniques), and evaluated with an objective to manage rice root-knot nematode (RRKN) (Meloidogyne graminicola) both under pluronic gel and field conditions. Out of these fourteen compounds, 1-(4-fluoro-phenyl)-3-phenyl-propenone (13) and 1,3-diphenyl-propenone (14) showed promising and dose dependent activity at 10, 20, and 40 mg L-1. A significant reduction in penetration of second stage juveniles (J2s) in rice roots was observed in compounds 13 (9.5-12.0 J2s/plant) and 14 (10.5-13.4 J2s/plant) compared to control plants (PB1121) (13.5-23.6 J2s/plant) in pluronic gel study. The results of field trials indicated that 14, showed significantly (P ≤ 0.05) better plant growth on 28 days after sowing (DAS) compared to 13. Both 13 and 14 reduced gall formation significantly than carbofuran 3 G @1 kg a.i./ha. However, lower concentrations were less effective in field in reducing the gall formation. Also, a significant reduction in the number of galls was observed when soil was drenched with 14 @ 40 mg L-1. However, root dipping was not as effective as soil drenching. The study revealed that both the chalcones have the potential for effective management of RRKN in fields, and can be a better alternative to carbofuran.

Synthesis, Biological Evaluation, and QSAR Studies of 3-Iodochromone Derivatives as Potential Fungicides.

Despite the emergence of novel biotechnological and biological solutions, agrochemicals continue to play an important role in crop protection. Fungicide resistance is becoming a major problem; numerous cases of fungicide resistance have occurred worldwide in the last decade, resulting in the loss of several fungicides. The discovery of new molecules has therefore assumed critical importance in crop protection. In our quest for biologically active molecules, we herein report the synthesis of a series of twenty-one 3-Iodochromone derivatives (4a-4u), in a two-step process by condensation of 2-hydroxyacetophenone derivatives (2a-2u) with N,N-dimethylformamidedimethylacetal yielding enaminones (3a-3u), followed by cyclization with iodine to corresponding 3-iodochromones. Characterization of these compounds was done by IR, 1H NMR, 13C NMR, and LC-HRMS techniques. All synthesized compounds were screened for their fungicidal activity against Sclerotium rolfsii. Among these 6,8-Dichloro-3-iodochromone 4r was found to be most active (ED50 = 8.43 mg L-1). 2D-Quantitative Structural Activity Relationship (2D-QSAR) analysis was also performed by generating three different models viz., Multiple Linear Regression (MLR, Model 1), Principal Component Regression (PCR, Model 2), and Partial Least Squares (PLS, Model 3). Predictive power and statistical significance of these models were assessed with external and internal validation and leave one-out cross-validation was used for verification. In QSAR study, MLR (Model 1) was found to be best having correlation coefficient (r2) 0.943, cross-validated correlation coefficient (q2) 0.911 and r2pred 0.837. It was observed that DeltaEpsilonC, T_2_Cl_6, T_2_F_6, T_T_F_3, and ZCompDipole are the major descriptors which influence the fungicidal activity of 3-Iodochromone derivatives. The physicochemical parameters were estimated by the VLifeMDS 4.6 software. The QSAR study results will be helpful for structure optimization to improve the activity.

Microwave assisted synthesis, characterization and biological activities of ferrocenyl chalcones and their QSAR analysis: Part II.

A series of ferrocenyl chalcones using acetylferrocene, with ferrocenyl group at the keto carbonyl group, and different aldehydes were synthesized and their bioefficacy evaluation was done against Sclerotium rolfsii, Alternaria solani and Meloidogyne incognita. In continuation of our quest for potent crop protection products, in the present study, a series of 18 substituted ferrocenyl chalcones were synthesized in which ferrocenyl group was attached to the aldehyde moiety, using ferrocenecarboxyaldehyde and different acetophenones by microwave method (MM) and conventional method (CM) [cf: MM 1 to 5 min; CM 12-40 h] and characterized by various techniques viz. IR, LC-HRMS, 1H-NMR and 13C-NMR. In vitro fungicidal activity showed that compound, (2E)-1-(5-Chloro-2-hydroxyphenyl)-3-ferrocenyl-prop-2-en-1-one (34) (ED50 = 21.50 mg L-1) was found to be most active against S. rolfsii and compound, (2E)-1-(4-Bromophenyl)-3-ferrocenyl-prop-2-en-1-one (21) (ED50 = 31.14 mg L-1) showed highest activity against A. solani. As regards nematicidal activity, compound (2E)-1-(3-Bromophenyl)-3-ferrocenyl-prop-2-en-1-one (29) was more potent with LC50 values of 11.95, 8.07 and 4.34 mg L-1 at 24, 48 and 72 h, respectively. QSAR study revealed that MLR for S. rolfsii (r 2 = 0.9834, q 2= 0.8975) and A. solani (r 2 = 0.9807, q 2= 0.8713) and PLS for M. incognita (r 2 = 0.9023, q 2= 0.7818) were the best models.

Amphiphilic polymer based nanoformulations of mancozeb for management of early blight in tomato.

Controlled release (CR) nanoformulations of Mancozeb (Manganese-zinc double salt of N, N-bisdithiocarbamic acid), a protective fungicide, have been developed using poly (ethylene glycols) (PEGs) based functionalized amphiphilic copolymers and evaluated for the management of early blight in tomato. During the field experiment, it was observed that number of infected leaflets/plants were less in developed formulation treated plants as compared to commercial products. Number of infected leaflets per plant was 2.40-4.60 and the number of fruits per plant were 6.40-9.00 at 50 mg L-1, whereas at 100 mg L-1, the corresponding numbers were 2.10-4.10 and 6.30-9.10 respectively. These formulations can be used to optimize the release of Mancozeb to achieve disease control for the desired period depending upon the matrix of the polymer used. Importantly, sufficient amount of active ingredient remains available for a reasonable period of time after application leading to reduced number of applications of pesticide.

Microwave Assisted Synthesis, Characterization and Biological Activities of Ferrocenyl Chalcones and Their QSAR Analysis.

A new microwave method (MM) has been developed for the synthesis of a series of 16 substituted ferrocenyl chalcones using acetylferrocene (1) with different aldehydes (2a-2p) and comparing it with conventional method (CM). The synthesized compounds were characterized by various spectroscopic techniques viz IR, HR-MS, 1H NMR, and 13C NMR. The time required for completion of reaction in MM varied from 1 to 5 min as compared to CM which required 10-40 h. All the synthesized compounds were screened for antifungal activity against Sclerotium rolfsii and Alternaria solani. In vitro fungicidal activity revealed that compound 3o (ED50 = 23.24 mg L-1) was found to be most active against S. rolfsii. But in case of A. solani, compound 3c (ED50 = 29.9 mg L-1) showed highest activity. The nematicidal activity revealed that the compound 3b was more potent with LC50 values of 10.67, 7.30, and 4.55 ppm at 24, 48, and 72 h, respectively. 2D-Quantitative Structural Activity Relationship (2D-QSAR) analysis of these ferrocenyl chalcones was carried out by developing three different models namely Partial Least Squares (PLS, Model 1), Multiple Linear Regression (MLR, Model 2) and Principal Component Regression (PCR, Model 3). Statistical significance and predictive ability of these models were assessed by internal and external validation and also verified by leave one-out cross-validation. QSAR study revealed that MLR for S. rolfsii (r 2 = 0.999, q 2 = 0.996), PLS for A. solani (r 2 = 0.934, q 2 = 0.749) and PCR for M. incognita (r 2 = 0.878, q 2 = 0.772) were the best model. The physico-chemical parameters were calculated using VLife MDS 4.6 software. QSAR study could be employed for structure optimization to achieve better activity.

Insecticidal activity of phenolic acid amides against brown planthopper (BPH), Nilaparvata lugens (Stål) and their QSAR analysis.

A series of 42 phenolic acid amides, synthesized using different phenolic acids (salicylic acid, 3-hydroxy cinnamic acid, p-coumaric acid, caffeic acid, ferulic acid, o-coumaric acid, cinnamic acid and amines (propyl amine, hexyl amine, heptyl amine, undecyl amine, hexadecyl amine, octadecyl amine) were screened for their insecticidal activities against Brown Planthopper (BPH), Nilaparvata lugens. These phenolic acid amides showed moderate to good insecticidal activity with the lowest LC50 value of 63.84 ppm from N-propyl-2-hydroxycinnamamide. 2D-Quantitative structural activity relationship (2D-QSAR) analysis of these phenolic acid amides was carried out by developing three different models namely multiple linear regression (MLR), principal component regression (PCR) and partial least squares (PLS). Statistical significance and predictive ability of these models were assessed by internal and external validation and verified by leave one-out cross-validation. PLS (model 3) was found best for QSAR study with correlation coefficient (r2) 0.8388, cross-validated correlation coefficient (q2) 0.7797 and r2 pred 0.7347. It was found that + vePotentialSurfaceArea, XAMostHydrophobic, SaasCE-index, T_O_O_3 and T_O_O_6 are the major descriptors which influence the insecticidal activities of these phenolic acid amides. The QSAR study could help in structural optimization of phenolic acid amides in developing potential compounds to get better bioefficacy against N. lugens.

Development of controlled release formulations of thiram employing amphiphilic polymers and their bioefficacy evaluation in seed quality enhancement studies.

Controlled release formulations of Thiram (Dimethylcarbamothioylsulfanyl-N,N-dimethylcarbamodithioate), a contact fungicide, have been prepared using laboratory synthesized poly(ethylene glycol) (PEG) based functionalized amphiphilic copolymers. The kinetics of thiram from developed controlled release (CR) formulations were studied in comparison with that of the commercially available 75 WS. Release from the commercial formulation was faster than with the developed CR formulations. Maximum amount of thiram was released on 35th day for PEG-2000 4d, 28th day for PEG-1500 4c, 21st day for PEG-1000 4b and 15th day for PEG-600 4a in comparison to commercial formulation (7th day). The diffusion exponent (n) of thiram in water ranged from 0.356 to 0.545 in the tested formulations. The half-release (t(1/2)) values ranged between 14.78 to 22.1 days, and the Period of Optimum Availability (POA) of thiram ranged from 7.79 to 25.15 days. An effort has also been made to identify the suitable polymers that could reduce the seed deterioration during storage and also act as an effective carrier of fungicide thiram. The results demonstrate that the seeds coated with the different formulations deteriorated at a slower pace as manifested in high germination percentage over control. Apart from the fungicidal effect of thiram, the polymers acted as barriers to moisture reducing the rate of seed deterioration and checked the degradation of thiram. The CR formulation 4d, with PEG 2000, was found to be most effective as seed coat.