Journal of Heterocyclic Chemistry最新文献

An efficient method for the synthesis of valuable terminal C7-alkenylated indolines through the direct C–H alkenylation of N-pyridinyl indolines in the presence of a rhodium catalyst has been developed. Alkenyl borates were first used as a useful alkenyl reagent for C–H functionalization of indolines. Under mild reaction conditions, a series of indolines with different functional groups were compatible in this transformation, affording the C7-alkenylated product in good to excellent yields. Moreover, the C7-alkenylated indoline can be conveniently converted to the pyrroloquinoline derivative, which is a popular tricyclic indoline skeleton in bioactive compounds, highlighting its potential application value.

Developing new pesticide led compounds to minimize the escalating resistance of agricultural pests which raised by the extensive use of agrochemicals is highly desirable. A series of novel heterocyclic tosyl esters was designed, synthesized, and characterized via different spectral analyses. The pesticidal potential of the thiazolidinone, thiazole, thiophene, and chromene derivatives against Aphis gossypii (Glover) and Tetranychus urticae (Koch) was assessed. The effect of the most potent derivatives on the enzyme activity of both tested pests was also examined. Thiazolidinone derivative 4 was the most effective against either pests, exhibiting significant pesticidal activity that was comparable to or superior to that of standard pesticides. The DFT study was performed for the most potent compounds. The results indicate that these recently synthesized compounds could be effective alternatives in pest controlling strategies.

Our research team has successfully synthesized BZR-cotoxin IV, despite encountering considerable difficulties stemming from its unique structural features. The molecule's ester bond is particularly susceptible to hydrolysis, which leads to instability during the synthesis process. Moreover, the tendency of its linear precursor to form diketopiperazine (DKP) adds another layer of complexity to the synthesis. To overcome these obstacles, we adopted a strategy centered on developing an analog compound. This approach was guided by structure–activity relationship (SAR) principles. The key modification involved substituting the hydroxy acid residue (Hiv) found in the original BZR-cotoxin IV with its corresponding amino acid, valine. This strategic alteration was intended to not only potentially improve the compound's characteristics but also to streamline the synthesis procedure. The synthesis of [Val]⁷-BZR-cotoxin IV was accomplished using a hybrid approach that combined solid-phase and solution-phase peptide synthesis techniques. The linear precursor of [Val]⁷-BZR-cotoxin IV was produced using Fmoc chemistry on CTC resin, with HATU/HOAt serving as the coupling reagent for amide bond formation. This process yielded a 9.25% pure product as a white powder. The cyclization step was performed using HATU in a dilute solution, which produced cyclic [Val]⁷-BZR-cotoxin IV with a yield of 12.9% as a white powder. Cytotoxicity test was conducted on both the linear and cyclic forms of [Val]⁷-BZR-cotoxin IV together with its natural BZR-cotoxin IV against HeLa cancer cells. The result showed moderate activity, with IC₅₀ values of 297.60 μM for the linear precursor and 161.58 μM for the cyclic analog. Notably, the cyclic [Val]⁷-BZR-cotoxin IV demonstrated higher cytotoxic activity compared with its natural counterpart, BZR-cotoxin IV, which had an IC₅₀ value of 214.01 μM.

Present study involves synthesis of derivatives of (5-chloro-2-methoxyphenyl) (5-alkyl-3-(substituted) (phenyl/alkyl)-1H-pyrazol-1-yl) methanones. Structural elucidation of the synthesized compounds was depicted by the data of ¹H and ¹³C NMR, IR, and Mass spectral analysis. The newly synthesized compounds 1a–1d and 2a–2i were screened in vitro against Mycobacterium tuberculosis H37Ra using an established XRMA protocol. Among the screened compounds, 2d, 2f, and 2h showed good percent inhibition against the active stage of M. tuberculosis H37Ra 80.77, 55.70, and 79.54, respectively, at 30 μg/mL of inhibitor concentration. Further in secondary screening, compound 2d exhibited significant antitubercular activity on the active stage of M. tuberculosis H37Ra with IC₅₀ of 0.208 μg/mL. The synthesized compounds were also screened for antibacterial activity and found no significant activity against Gram-positive Bacteria Bacillus subtitles and Staphylococcus aureus and Gram negative bacteria Pseudomonas aeruginosa and Escherichia coli at 30 μg/mL, which confirms the specificity of inhibitory activity against M. tuberculosis and more selectively against the active stage. The present study will be helpful for the further development of these molecules into antitubercular lead candidates.

A four-component one-pot sequential approach to five-membered oxaphosphaheterocycles have developed. The method involves in situ generation of methylpyrazolin-5-one from ethyl acetoacetate and phenyl hydrazine. Further, a sequential reaction of methylpyrazolin-5-one with various aromatic aldehydes and phenyl dichloro phosphine afforded dihydro oxaphospholo pyrazole 2-oxide derivatives.

Using pyrimidinethione, a new series of pyridinyl-pyrimidine candidates was prepared by reacting with diverse carbon-centered electrophiles like hydrazonoyl chloride, N-arylchloroacetamide, ethyl chloroacetate, and enaminone derivatives. Some heteroannulated compounds, such as triazolopyrimidine and thiazolopyrimidine derivatives were obtained. The mass fragmentation pathways were investigated by the electron impact mass spectrometry (EI-MS), and the molecular ion peaks (M^+.) were recorded at different intensities. The in vitro antiproliferative efficacy of the prepared compounds against MCF7 and HCT116 cancer cell lines showed the highest potency of pyrimidinethione 2, triazolopyrimidine 4, and thiazolopyrimidine 10. Also, in silico studies were performed to recognize these findings. A molecular docking simulation towards the EGFR enzyme showed the best docking score of thiazolopyrimidine 10 through H-bonding and hydrophobic interactions in comparison to the interactions of co-crystallized ligand and doxorubicin. With DFT calculations, compound 10 exhibited the lowest energy gap and the highest softness. Among ADME simulation, compounds 7, 8, 9, and 11 exhibited desirable lead-likeness. It is hoped that this work may affect advancing new effective antiproliferative agents.

In this study, a novel ring system, benzo[6,7]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-9-amines was efficiently synthesized. For that, 4-(aryl)-2-thioxo-2,5,6,7-tetrahydro-1H-benzo[6,7]cyclohepta[1,2-b]pyridine-3-carbonitriles were chosen as valuable intermediates. These synthons were reacted with the respective hydrazonyl chlorides in ethanol in the presence of triethylamine. The reaction was stirred at 50°C for 1–1.5 to afford a novel series of 2-oxo-N-phenylpropanehydrazonothioates in 82%–89% yields. Heating of the previous hydrazonothioates in an ethanolic sodium ethanolate solution under reflux for 2–3 h yielded a novel series of 8,11-diphenyl-5,6,7,11-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-9-amines in 77%–86% yields. The structures of the novel products were elucidated by elemental-analyses and spectral data.

To explore novel structures of strobilurin fungicides, a series of novel strobilurin derivatives featuring a substituted 1,3,4-oxadiazole in the side chain were synthesized using an intermediate derivatization method and characterized by nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry (HRMS). The reactions involved in the synthesis process include hydrazine hydrolysis, cyclization, nucleophilic substitution reactions. The raw materials required for these reactions are readily available, and the procedures involved in the reaction process are straightforward. The fungicidal activities of the compounds were tested using the inhibition zone method. The inhibition rate of compound 5f on Magnaporthe oryzae was 81.8% at a concentration of 3.125 mg/L, and the EC₅₀ value (0.3045 mg/L) was better than superior to that of kresoxim-methyl (0.5247 mg/L).

Cyclic ether-fused tricyclic naphthoquinones are major pharmacophores because of their biological activities. The methodology of construction is either by inter or intra-molecular cyclization of functionalized naphthoquinones. This reaction includes a wide range of reagents from classical Brønsted to Lewis acids. The choice of appropriate reagent and reaction conditions against the substrate is the key to accomplishing the regio- and/or stereo-selective synthesis of these compounds, though it seems difficult at first glance to decide how because numerous numbers of actual examples have been presented. To have a deeper insight into the mechanism of cyclization under acid conditions, lapachol 1 was subjected to electrophilic entities: Brønsted acids (H₂SO₄, HCl, H₃PO₄, HNO₃, HCOOH, CH₃COOH, HOOCCH₂COOH), Lewis acids (AlCl₃, FeCl₃, ZnCl₂) nitrogenous cations (NO⁺, NO²⁺), carbocation (CH₃CO⁺), neutral polarized molecules (CH₃COCl, CH₃COOCH₃), neutral polarizable molecules (Br₂, I₂), oxidant promoted cyclization (DDQ, CAN, Peroxides), and reaction conditions. A series of Naphthoquinones based on the Isoprenyl-1,4-naphthoquinone (Lapachol), naphtho[1,2-b]furan-4,5-dione (nor β-lapachone), naphtho[2,3-b]pyran-5,10-dione (α-lapachone), naphtho[1,2-b]pyran-5,6-dione (β-lapachone), and naphtho[2,3-b]furan-4,9-dione (2-acetyl furonaphthoquinone) skeletons were selectively synthesized. By looking at our result, there are characteristic trends of cyclized adducts depending on which reagents were used. The synthesized compounds were evaluated for their biological activity against the MDA-MB-231 breast cancer, HT-29 MTX colon cancer, and non-transformed mammary epithelial cell lines at concentrations of 1 μM, 10 μM, and 100 μM. The result indicated that lapachol and β-lapachone skeletons were the most active at 10 μM and 100 μM especially 3-hydroxy-β-lapachone 8 with interesting growth stimulatory effect on cancer cell lines, but not the non-transformed cells.