Synthesis, antifungal activity and 3D-QSAR study of novel acyl thiourea compounds containing gem-dimethylcyclopropane ring.

A series of novel acyl thiourea compounds containing gem-dimethylcyclopropane ring were designed and synthesized by multi-step reactions in search of novel antifungal molecules. Structures of all the target compounds were characterized by spectral techniques of UV-vis, FT-IR, 1H-NMR, 13C-NMR, and ESI-MS. The antifungal activity of the target compounds was preliminarily evaluated by agar dilution method. The antifungal bioassay revealed that, at 50 µg/mL, compounds 5h (R = o-F), 5m (R = p-Br), and 5n (R = o-NO2) showed the same antifungal activity of 73.6% against Physalospora piricola, which was comparable than that of the positive control. Furthermore, against Gibberella zeae, compounds 5k (R = m-Cl), 5l (R = m-Br), 5m (R = p-Br), and 5n (R = o-NO2) displayed the same antifungal activity of 75.6%, and compound 5o (R = p-NO2) displayed antifungal activity of 78.8%, which were all better than that of the positive control. The preliminary analysis of 3D-QSAR model was performed to study the effect of molecular structure on biological activity using the comparative molecular field analysis (CoMFA) method. The results showed 3D-QSAR model (r2 = 0.995, q2 = 0.503) was reasonable and effective.

Synthesis, Antifungal Activity, 3D-QSAR, and Molecular Docking Study of Novel Menthol-Derived 1,2,4-Triazole-thioether Compounds.

A series of novel menthol derivatives containing 1,2,4-triazole-thioether moiety were designed, synthesized, characterized structurally, and evaluated biologically to explore more potent natural product-based antifungal agents. The bioassay results revealed that at 50 µg/mL, some of the target compounds exhibited good inhibitory activity against the tested fungi, especially against Physalospora piricola. Compounds 5b (R = o-CH3 Ph), 5i (R = o-Cl Ph), 5v (R = m,p-OCH3 Ph) and 5x (R = α-furyl) had inhibition rates of 93.3%, 79.4%, and 79.4%, respectively, against P. piricola, much better than that of the positive control chlorothalonil. Compounds 5v (R = m,p-OCH3 Ph) and 5g (R = o-Cl Ph) held inhibition rates of 82.4% and 86.5% against Cercospora arachidicola and Gibberella zeae, respectively, much better than that of the commercial fungicide chlorothalonil. Compound 5b (R = o-CH3 Ph) displayed antifungal activity of 90.5% and 83.8%, respectively, against Colleterichum orbicalare and Fusarium oxysporum f. sp. cucumerinum. Compounds 5m (R = o-I Ph) had inhibition rates of 88.6%, 80.0%, and 88.0%, respectively, against F. oxysporum f. sp. cucumerinu, Bipolaris maydis and C. orbiculare. Furthermore, compound 5b (R = o-CH3 Ph) showed the best and broad-spectrum antifungal activity against all the tested fungi. To design more effective antifungal compounds against P. piricola, 3D-QSAR analysis was performed using the CoMFA method, and a reasonable 3D-QSAR model (r2 = 0.991, q2 = 0.514) was established. The simulative binding pattern of the target compounds with cytochrome P450 14α-sterol demethylase (CYP51) was investigated by molecular docking.

Synthesis, Antifungal Activity, and 3D-QSAR Study of Novel Nopol-Derived 1,3,4-Thiadiazole-Thiourea Compounds.

A series of novel nopol derivatives bearing the 1,3,4-thiadiazole-thiourea moiety were designed and synthesized by multi-step reactions in search of potent natural product-based antifungal agents. Their structures were confirmed by FT-IR, NMR, ESI-MS, and elemental analysis. Antifungal activity of the target compounds was preliminarily evaluated by in vitro methods against Fusarium oxysporum f. sp. cucumerinum, Cercospora arachidicola, Physalospora piricola, Alternaria solani, Gibberella zeae, Rhizoeotnia solani, Bipolaris maydis, and Colleterichum orbicalare at 50 µg/mL. All the target compounds exhibited better antifungal activity against P. piricola, C. arachidicola, and A. solani. Compound 6j (R = m, p-Cl Ph) showed the best broad-spectrum antifungal activity against all the tested fungi. Compounds 6c (R = m-Me Ph), 6q (R = i-Pr), and 6i (R = p-Cl Ph) had inhibition rates of 86.1%, 86.1%, and 80.2%, respectively, against P. piricola, much better than that of the positive control chlorothalonil. Moreover, compounds 6h (R = m-Cl Ph) and 6n (R = o-CF3 Ph) held inhibition rates of 80.6% and 79.0% against C. arachidicola and G. zeae, respectively, much better than that of the commercial fungicide chlorothalonil. In order to design more effective antifungal compounds against A. solani, analysis of the three-dimensional quantitative structure-activity relationship (3D-QSAR) was carried out using the CoMFA method, and a reasonable and effective 3D-QSAR model (r2 = 0.992, q2 = 0.753) has been established. Furthermore, some intriguing structure-activity relationships were found and are discussed by theoretical calculation.

Synthesis and Antiproliferative Evaluation of Novel Longifolene-Derived Tetralone Derivatives Bearing 1,2,4-Triazole Moiety.

Seventeen novel 2-(5-amino-1-(substituted sulfonyl)-1H-1,2,4-triazol-3-ylthio)-6- isopropyl-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one compounds were synthesized from the abundant and naturally renewable longifolene and their structures were confirmed by FT-IR, NMR, and ESI-MS. The in vitro cytotoxicity of the synthesized compounds was evaluated by standard MTT assay against five human cancer cell lines, i.e., T-24, MCF-7, HepG2, A549, and HT-29. As a result, compounds 6d, 6g, and 6h exhibited better and more broad-spectrum anticancer activity against almost all the tested cancer cell lines than that of the positive control, 5-FU. Some intriguing structure-activity relationships were found and are discussed herein by theoretical calculation.

Synthesis and Antiproliferative Evaluation of Novel Hybrids of Dehydroabietic Acid Bearing 1,2,3-Triazole Moiety.

To discover novel potent cytotoxic diterpenoids, a series of hybrids of dehydroabietic acid containing 1,2,3-triazole moiety were designed and synthesized. The target compounds were characterized by means of FT-IR, 1H NMR, 13C NMR, ESI-MS and elemental analysis techniques. The in vitro cytotoxicity of these compounds was evaluated by standard MTT (methyl thiazolytetrazolium) assay against CNE-2 (nasopharynx), HepG2 (liver), HeLa (epithelial cervical), BEL-7402 (liver) human carcinoma cell lines and human normal liver cell (HL-7702). The screening results revealed that most of the hybrids showed significantly improved cytotoxicity over parent compound DHAA. Among them, [1-(3-fluorobenzyl)-1H-1,2,3-triazole-4-yl]dehydroabietic acid methyl ester (3c), and [1-(2-nitrobenzyl)-1H-1,2,3-triazole-4-yl]dehydroabietic acid methyl ester (3k) displayed better antiproliferative activity with IC50 (50% inhibitory concentration) values of 5.90 ± 0.41 and 6.25 ± 0.37 µM toward HepG2 cells compared to cisplatin, while they exhibited lower cytotoxicity against HL-7702. Therefore, the 1,2,3-triazole-hybrids could be a promising strategy for the synthesis of antitumor diterpenoids and it also proved the essential role of 1,2,3-triazole moiety of DHAA in the biological activity.

Recognition Selectivities of Lasso-Type Pseudo[1]rotaxane Based on a Mono-Ester-Functionalized Pillar[5]arene.

Two types of mono-ester-functionalized pillar[5]arenes, P1 and P2, bearing different side-chain groups, were synthesized. Their host-guest complexation and self-inclusion properties were studied by 1H NMR and 2D nuclear overhauser effect spectroscopy (NOESY) NMR measurements. The results showed that the substituents on their phenolic units have a great influence on the self-assembly of both pillar[5]arenes, although they both could form stable pseudo[1]rotaxanes at room temperature. When eight bulky 4-brombutyloxy groups were capped on the cavity, instead of methoxy groups, pseudo[1]rotaxane P1 became less stable and its locked ester group in the inner space of cavity was not as deep as P2, leading to distinctly different host-guest properties between P1 and P2 with 1,6-dibromohexane. Moreover, pillar[5]arene P1 displayed effective molecular recognition toward 1,6-dichlorohexane and 1,2-bromoethane among the guest dihalides. In addition, the self-complex models and stabilities between P1 and P2 were also studied by computational modeling and experimental calculations.

Synthesis of Bioactive Compounds from 3-Carene (II): Synthesis, Antifungal Activity and 3D-QSAR Study of (Z)- and (E)-3-Caren-5-One Oxime Sulfonates.

A series of novel (Z)- and (E)-3-caren-5-one oxime sulfonates were designed and synthesized in search of potent antifungal agents. The structures of the intermediates and target compounds were confirmed by UV-Vis, FTIR, NMR, and ESI-MS. The in vitro antifungal activity of the target compounds was preliminarily evaluated against Cercospora arachidicola, Physalospora piricola, Alternaria solani, Rhizoeotnia solani, Bipolaris maydis and Colleterichum orbicalare at 50 µg/mL. The bioassay results indicated that the target compounds exhibited the best antifungal activity against P. piricola, in which compounds 4b, 4f, 4m, 4e, 4j, 4l, 4y, 4d, and 4p had excellent inhibition rates of 100%, 100%, 100%, 92.9%, 92.9%, 92.9%, 92.9%, 85.7%, and 85.7%, respectively, showing much better antifungal activity than that of the commercial fungicide chlorothanil. Both the compounds 4y and 4x displayed outstanding antifungal activity of 100% against B. myadis, and the former also displayed outstanding antifungal activity of 100% against R. solani. In order to design more effective antifungal compounds against P. piricola, the analysis of three-dimensional quantitative structure-activity relationship (3D-QSAR) was carried out using the CoMFA method, and a reasonable and effective 3D-QSAR model (r² = 0.990, q² = 0.569) has been established.

Synthesis of Nitrogen-Rich Polymers by Click Polymerization Reaction and Gas Sorption Property.

Microporous organic polymers (MOPs) are promising materials for gas sorption because of their intrinsic and permanent porosity, designable framework, and low density. The introduction of nitrogen-rich building block in MOPs will greatly enhance the gas sorption capacity. Here, we report the synthesis of MOPs from the 2,4,6-tris(4-ethynylphenyl)-1,3,5-triazine unit and aromatic azides linkers by click polymerization reaction. Fourier transform infrared (FTIR) and solid-state 13C CP-MAS (Cross Polarization-Magic Angle Spinning) NMR confirm the formation of the polymers. CMOP-1 and CMOP-2 exhibit microporous networks with a BET (Brunauer⁻Emmett⁻Teller) surface area of 431 m²·g-1 and 406 m²·g-1 and a narrow pore size distribution under 1.2 nm. Gas sorption isotherms including CO2 and H2 were measured. CMOP-1 stores a superior CO2 level of 1.85 mmol·g-1 at 273 K/1.0 bar, and an H2 uptake of up to 2.94 mmol·g-1 at 77 K/1.0 bar, while CMOP-2, with its smaller surface area, shows a lower CO2 adsorption capacity of 1.64 mmol·g-1 and an H2 uptake of 2.48 mmol·g-1. In addition, I2 vapor adsorption was tested at 353 K. CMOP-1 shows a higher gravimetric load of 160 wt%. Despite the moderate surface area, the CMOPs display excellent sorption ability for CO2 and I2 due to the nitrogen-rich content in the polymers.

Synthesis and Biological Activity of Novel (Z)- and (E)-Verbenone Oxime Esters.

Twenty-seven (Z)- and (E)-verbenone derivatives bearing an oxime ester moiety were designed and synthesized in search of novel bioactive molecules. Their structures were confirmed by UV-Vis, FTIR, NMR, ESI-MS, and elemental analysis. The antifungal and herbicidal activities of the target compounds were preliminarily evaluated. As a result, compound (E)-4n (R = ß-pyridyl) exhibited excellent antifungal activity with growth inhibition percentages of 92.2%, 80.0% and 76.3% against Alternaria solani, Physalospora piricola, and Cercospora arachidicola at 50 µg/mL, showing comparable or better antifungal activity than the commercial fungicide chlorothalonil with growth inhibition of 96.1%, 75.0% and 73.3%, respectively, and 1.7-5.5-fold more growth inhibition than its stereoisomer (Z)-4n (R = ß-pyridyl) with inhibition rates of 22.6%, 28.6% and 43.7%, respectively. In addition, seven compounds displayed significant growth inhibition activity of over 90% against the root of rape (Brassica campestris) at 100 µg/mL, exhibiting much better herbicidal activity than the commercial herbicide flumioxazin with a 63.0% growth inhibition. Among these seven compounds, compound (E)-4n (R = ß-pyridyl) inhibited growth by 92.1%, which was 1.7-fold more than its stereoisomer (Z)-4n (R = ß-pyridyl) which inhibited growth by 54.0%.

Synthesis and Antifungal Activity of Novel 3-Caren-5-One Oxime Esters.

A series of novel 3-caren-5-one oxime esters were designed and synthesized by multi-step reactions in an attempt to develop potent antifungal agents. Two E-Z stereoisomers of the intermediate 3-caren-5-one oxime were separated by column chromatography for the first time. The structures of all the intermediates and target compounds were confirmed by UV-Vis, FTIR, NMR, ESI-MS, and elemental analysis. The antifungal activity of the target compounds was preliminarily evaluated by the in vitro method against Fusarium oxysporum f. sp. cucumerinum, Physalospora piricola, Alternaria solani, Cercospora arachidicola, Gibberella zeae,Rhizoeotnia solani, Bipolaris maydis, and Colleterichum orbicalare at 50 µg/mL. The target compounds exhibited best antifungal activity against P. piricola, in which compounds (Z)-4r (R = ß-pyridyl), (Z)-4q (R = α-thienyl), (E)-4f' (R = p-F Ph), (Z)-4i (R = m-Me Ph), (Z)-4j (R = p-Me Ph), and (Z)-4p (R = α-furyl) had inhibition rates of 97.1%, 87.4%, 87.4%, 85.0%, 81.9%, and 77.7%, respectively, showing better antifungal activity than that of the commercial fungicide chlorothanil. Also, compound (Z)-4r (R = ß-pyridyl) displayed remarkable antifungal activity against all the tested fungi, with inhibition rates of 76.7%, 82.7%, 97.1%, 66.3%, 74.7%, 93.9%, 76.7% and 93.3%, respectively, showing better or comparable antifungal activity than that of the commercial fungicide chlorothanil. Besides, the E-Z isomers of the target oxime esters were found to show obvious differences in antifungal activity. These results provide an encouraging framework that could lead to the development of potent novel antifungal agents.

Synthesis and In Vitro Anticancer Activity of Novel Dehydroabietic Acid-Based Acylhydrazones.

In order to develop novel chemotherapeutic agents with potent anticancer activities, a series of dehydroabietic acid (DHA) derivatives bearing an acylhydrazone moiety were designed and synthesized by the condensation between dehydroabietic acylhydrazide (3) and a variety of substituted arylaldehydes. The inhibitory activities of these compounds against CNE-2 (nasopharynx), HepG2 (liver), HeLa (epithelial cervical), and BEL-7402 (liver) human carcinoma cell lines were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in vitro. The screening results revealed that many of the compounds showed moderate to high levels of anticancer activities against the tested cancer cell lines and some displayed similar potent inhibitory activities to the commercial anticancer drug cisplatin, while they exhibited lower cytotoxicity against normal human liver cell (HL-7702). Particularly, compound 4w, N'-(3,5-difluorobenzylidene)-2-(dehydroabietyloxy)acetohydrazide, with an IC50 (50% inhibitory concentration) value of 2.21 µM against HeLa cell, was about 17-fold more active than that of the parent compound, and showed remarkable cytotoxicity with an IC50 value of 14.46 µM against BEL-7402 cell. These results provide an encouraging framework that could lead to the development of potent novel anticancer agents.

Synthesis and Antifungal Activity of Novel Myrtenal-Based 4-Methyl-1,2,4-triazole-thioethers.

A series of novel myrtenal derivatives bearing 1,2,4-triazole moiety were designed and synthesized by multi-step reactions in an attempt to develop potent antifungal agents. Their structures were confirmed by using UV-vis, FTIR, NMR, and ESI-MS analysis. Antifungal activity of the target compounds was preliminarily evaluated by the in vitro method against Fusarium oxysporum f. sp. cucumerinum, Physalospora piricola, Alternaria solani, Cercospora arachidicola, and Gibberella zeae at 50 µg/mL. Compounds 6c (R = i-Pr), 6l (R = o-NO2 Bn), and 6a (R = Et) exhibited excellent antifungal activity against P. piricola with inhibition rates of 98.2%, 96.4%, and 90.7%, respectively, showing better or comparable antifungal activity than that of the commercial fungicide azoxystrobin with a 96.0% inhibition rate, which served as a positive control.

rac-(1R,2S,6R,7R)-4-{[(1E)-(2-Chloro-phen-yl)methyl-idene]amino}-1-isopropyl-7-methyl-4-aza-tricyclo-[5.2.2.0]undec-8-ene-3,5-dione.

The title compound, C(21)H(23)ClN(2)O(2), was synthesized from N-amino-α-terpinene maleimide and 2-chloro-benzaldehyde. There are two independent mol-ecules in the asymmetric unit which are linked via an inter-molecular C-H⋯O hydrogen bond. The crystal studied was found to be a partial merohedral twin, with a 0.74 (7):0.26 (7) domain ratio.