Synthesis and antitumor activities of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety

A series of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety were designed, synthesized and evaluated for their in vitro antitumor activities against SMMC-7721, MCF-7 and A549 human tumor cell lines by CCK-8 assay. The bioassay results demonstrated that most of the tested compounds showed potent antitumor activities, and some compounds exhibited stronger effects than positive control 5-fluorouracil (5-FU) against various cell lines. Among these compounds, compound 8d showed the best inhibitory effect against SMMC-7721 cells, with IC₅₀ value of 2.84 μM. Compounds 8k and 8n displayed highly effective antitumor activities against MCF-7 cells, with IC₅₀ values of 4.56 and 4.25 μM, respectively. Compounds 8a and 8n exhibited significant antiproliferative activity against A549 cells, with IC₅₀ values of 4.11 and 4.13 μM, respectively. The pharmacological results suggest that the substituents of phenyl ring on the 1,3,4-oxadiazole are vital for modulating antiproliferative activities against various tumor cell lines.     

Molecular docking studies and biological evaluation of 1,3,4-thiadiazole derivatives bearing Schiff base moieties as tyrosinase inhibitors

1,3,4-Thiadiazole derivatives bearing Schiff base moieties were designed, synthesized, and their tyrosinase inhibitory activities were evaluated. Some compounds displayed potent tyrosinase inhibitory activities, especially, 4-(((5-mercapto-1,3,4-thiadiazol-2-yl)-imino)methyl)-2-methoxy-phenol (14) exhibited superior inhibitory effect to the other compounds with an IC₅₀ value of 0.036 μM. The structure–activity relationships (SARs) were preliminarily discussed and docking studies showed compound 14 had strong binding affinity to mushroom tyrosinase. Hydroxy might be the active groups. The inhibition kinetics study revealed that compounds (13 and 14) inhibited tyrosinase by acting as uncompetitive inhibitors. The LD₅₀ value of the compound 14 was 5000 mg/kg.     

Novel amide derivatives containing 1,3,4-thiadiazole moiety: Design,synthesis, nematocidal and antibacterial activities

A series of novel amide derivatives containing 1,3,4-thiadiazole moiety were synthesized and their bioactivities were evaluated. The compound 34 exhibited good nematocidal activities against Meloidogyne incognita in vitro and in vivo, the LC₅₀ value and control effect were 6.5?mg/L and 83.3%, respectively. Meanwhile, it exhibited exciting antibacterial activities against Xanthomonas oryzae pv. oryzae, Xanthomonas campestris pv. citri, and Ralstonia solanacearum, the EC₅₀ values were 0.4, 6.7 and 5.1?mg/L, respectively, which were better than positive controls. The curative and protection activities under the greenhouse conditions of compound 34 against rice bacterial blight were 47.9 and 55.8%, respectively. The structure-activity relationship were analyzed in detail.     

Synthesis and anticholinesterase activities of novel 1,3,4-thiadiazole based compounds

In the present study, new (1,3,4-thiadiazol-2-yl)benzene-1,3-diol based compounds have been synthesized and their potential anticholinesterases properties have been investigated using the modified of Ellman’s spectrophotometric method. The compounds were obtained by the reaction of hydrazides or thiosemicarbazides with aryl-modified sulfinylbis[(2,4-dihydroxyphenyl)methanethione]s. Their chemical structures were elucidated by IR, ¹H-NMR, ¹³C-NMR and EI-MS spectral data and elemental analyses. Most of the compounds acted as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors in vitro, with IC₅₀ values ranging from >500 to 0.053 μM and from >500 to 0.105 μM, respectively. The most potent compound 9 (IC₅₀ = 0.053 μM) proved to be selective toward AChE, exhibiting selectivity ratios versus BuChE of ca. 950. The kinetic studies showed that it is a mixed-type of AChE inhibitor. Another compound (2) was active against both enzymes with IC₅₀ values in the low nM range. The structure-activity relationships (SARs) of the compounds under consideration were discussed.     

Synthesis of matrinic amide derivatives containing 1,3,4-thiadiazole scaffold as insecticidal/acaricidal agents

In continuation of our program aimed at the development of natural product-based pesticidal agents, a series of matrinic amide derivatives containing 1,3,4-thiadiazole scaffold were prepared, and their insecticidal and acaricidal activities were evaluated against Mythimna separata and Tetranychus cinnabarinus. Some compounds exhibited potent insecticidal and acaricidal activities. It suggested that R¹ as a nitro group and R² as a fluorine atom, were important for the insecticidal activity; R¹ as the electron-donating groups and R² as the methyl group, were necessary for the acaricidal activity.     

Novel vanillin derivatives containing a 1,3,4-thiadiazole moiety as potential antibacterial agents

In this study, thirty-four novel vanillin derivatives containing a 1,3,4-thiadiazole structure were obtained and their antibacterial activities were evaluated. The results indicate that most of the title compounds displayed inhibitory effects on Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas oryzae pv. oryzicola (Xoc). Among them, compound 29 exhibited excellent antibacterial activities against Xoo and Xoc in vitro, with the EC₅₀ values of 3.14 and 8.83 μg/mL, respectively, much superior to thiodiazole copper (87.03 and 108.99 μg/mL) and bismerthiazol (67.64 and 79.26 μg/mL). Under greenhouse condition, the protective efficiency of compound 29 against rice bacterial leaf blight was 49.34%, and curative efficiency was 40.96%. In addition, compound 29 can reduce the exopolysaccharides production of Xoo, increase the permeability of cell membrane and damage cell membrane.     

Synthesis and antitrypanosomal profile of new functionalized 1,3,4-thiadiazole-2-arylhydrazone derivatives, designed as non-mutagenic megazol analogues

In this work we reported the synthesis and the trypanocidal profile of new 1,3,4-thiadiazole-2-arylhydrazone derivatives of nitroimidazole series (4) or phenyl series (5), designed by exploring the molecular hybridization approach between megazol (2) and guanyl hydrazone derivative (3). The evaluation of the activity against bloodstream trypomastigote forms of Trypanosoma cruzi forms lead us to identify a new potent trypamomicide prototype, that is, brazilizone A (4k), which present an IC₅₀/24 h = 5.3 μM.     

Synthesis and antitumor-evaluation of 1,3,4-thiadiazole-containing benzisoselenazolone derivatives

A series of novel 1,3,4-thiadiazole-containing benzisoselenazolone derivatives were prepared by the condensation of 2-chloroselenobenzoyl chloride and 2-amino-5-substituted-1,3,4-thiadiazole. Their in vitro antiproliferative activities were evaluated in SSMC-7721, MCF-7 and A-549 cells. The results suggest that, in different tumor cells, some compounds have good antiproliferative activity, certain selectivity and potential value of further research.     

Synthesis of (1,3,4-thiadiazol-2-yl)-acrylamide derivatives as potential antitumor agents against acute leukemia cells

A lead compound with the (1,3,4-thiadiazol-2-yl)-acrylamide scaffold was discovered to have significant cytotoxicity on several tumor cell lines in an in-house cell-based screening. A total of 60 derivative compounds were then synthesized and tested in a CCK-8 cell viability assay. Some of them exhibited improved cytotoxic activities. The most potent compounds had IC₅₀ values of 1–5 μM on two acute leukemia tumor cell lines, i.e. RS4;11 and HL-60. Flow cytometry analysis of several active compounds and detection of caspase activation indicated that they induced caspase-dependent apoptosis. It was also encouraging to observe that these compounds did not have obvious cytotoxicity on normal cells, i.e. IC₅₀ > 50 μM on HEK-293T cells. Although the molecular targets of this class of compound are yet to be revealed, our current results suggest that this class of compound represents a new possibility for developing drug candidates against acute leukemia.     

Microwave-assisted efficient synthesis of glucose-based 3-acetyl-5-alkyl-2,3-dihydro-1,3,4-oxadiazole derivatives catalyzed by sodium acetate

A novel approach to synthesize glucose-based 3-acetyl-5-alkyl-2,3-dihydro-1,3,4-oxadiazoles with the assistance of microwave irradiation was developed. The effects of different catalysts on the heterocyclization process were investigated, and the reaction conditions were optimized, with NaOAc emerging as the catalyst of choice. Under the optimized conditions, a series of novel 3-acetyl-5-alkyl-2,3-dihydro-1,3,4-oxadiazole derivatives 4 and 5 were successfully synthesized from hydrazones 2 and 3. The absolute configurations of hydrazones 2, 3 and oxadiazoles 4, 5 were confirmed by NMR spectroscopic data. The ratio of the isomers 4 and 5 was 1:1.     

Synthesis and antileishmanial activity of 5-(5-nitroaryl)-2-substituted-thio-1,3,4-thiadiazoles

A series of novel 2-substituted-thio-1,3,4-thiadiazoles bearing a 5-nitroaryl moiety including nitrofuran, nitrothiophene or nitroimidazole at the 5-position and a bulky residue attached to the 2-position of the thiadiazole ring were synthesised as potential antileishmanial agents. The target compounds were evaluated against the promastigote form of Leishmania major using the tetrazolium bromide salt (MTT) colorimetric assay. All test compounds exhibited high activity against L. major promastigotes with 50% inhibitory concentrations (IC₅₀) ranging from 1.11 to 3.16 μM. The structure-activity relationship study indicated that the S-pendant group attached to the 2-position of the thiadiazole ring has a high flexibility for structural alteration therefore retaining good antileishmanial activity.     

Synthesis and evaluation of a class of 1,4,7-triazacyclononane derivatives as iron depletion antitumor agents

Iron depletion has been confirmed as an efficient strategy for cancer treatment. In the current study, a series of 1,4,7-triazacyclononane derivatives HE-NO2A, HP-NO2A and NE2P2A, as well as the bifunctional chelators p-NO₂-PhPr-NE3TA and p-NH₂-PhPr-NE3TA were synthesized and evaluated as iron-depleting agents for the potential anti-cancer therapy against human hepatocellular carcinoma. The cytotoxicity of these chelators was measured using hepatocellular cancer cells and compared with the clinically available iron depletion agent DFO and the universal metal chelator DTPA. All these 1,4,7-triazacyclononane-based chelators exhibited much stronger antiproliferative activity than DFO and DTPA. Among them, chelators with phenylpropyl side chains, represented by p-NO₂-PhPr-NE3TA and p-NH₂-PhPr-NE3TA, displayed the highest antiproliferative activity against HepG2 cells. Hence, these compounds are attractive candidates for the advanced study as iron depletion agents for the potential anti-cancer therapy, and could be further in conjugation with a targeting moiety for the future development in targeted iron depletion therapy.     

Synthesis and antioxidant activity of novel Mannich base of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan

A new series of Mannich base of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan (6a–6ae) were synthesized and characterized by ¹H NMR, ESI-MS and elemental analysis. The structure of 6b was further confirmed by single crystal X-ray diffraction. All these novel compounds were screened for their in vitro antioxidant activity employing 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH), 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS⁺) and ferric reducing antioxidant power (FRAP) scavenging assays. Due to the combination of 1,4-benzodioxan, 1,3,4-oxadiazoles and substituted phenyl ring, most of them exhibited nice antioxidant activities. In all of these three assays mentioned above, compounds 6f and 6e showed significant radical scavenging ability comparable to the commonly used antioxidants, BHT and Trolox. Seven compounds with representative substituents or activities were selected for further assays in chemical simulation biological systems—inhibition of microsomal lipid peroxidation (LPO) and protection against 2,2′-azobis (2-amidinopropane hydrochloride) (AAPH) induced DNA strand breakage, in which, 6f and 6e were demonstrated to be of the most potent antioxidant activities.     

Synthesis, biological evaluation and molecular docking studies of 1,3,4-thiadiazole derivatives containing 1,4-benzodioxan as potential antitumor agents

A series of 1,3,4-thiadiazole derivatives containing 1,4-benzodioxan (2a-2s) have been synthesized to screen for FAK inhibitory activity. Compound 2p showed the most potent biological activity against HEPG2 cancer cell line (EC(50)=10.28 μg/mL for HEPG2 and EC(50)=10.79 μM for FAK), which was comparable to the positive control. Docking simulation was performed to position compound 2p into the FAK structure active site to determine the probable binding model. The results of antiproliferative and Western-blot assay demonstrated that compound 2p possessed good antiproliferative activity against HEPG2 cancer cell line. Therefore, compound 2p with potent FAK inhibitory activity may be a potential anticancer agent against HEPG2 cancer cell.     

Synthesis,characterization, and antimicrobial evaluation of some new hydrazinecarbothioamide, 1,2,4-triazole and 1,3,4-thiadiazole derivatives

In this work, we reported the synthesis and evaluation of antibacterial and antifungal activities of three new compound series obtained from 6-(phenyl/4-chlorophenyl)imidazo[2,1-b]thiazole-3-acetic acid hydrazide: 2-{[6-(phenyl/4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]acetyl}-N-alkyl/arylhydrazinecarbothioamides (2a–d), 4-alkyl/aryl-2,4-dihydro-5-{[6-(phenyl/4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]methyl}-3H-1,2,4-triazole-3-thiones (3a–n), and 2-alkyl/arylamino-5-{[6-(phenyl/4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]methyl}-1,3,4-thiadiazoles (4a–g). The newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR (APT), mass and elemental analysis. Their antibacterial and antifungal activities were evaluated against Staphylococcus aureus ATCC 29213, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, Candida albicans ATCC 10231, C. parapsilosis ATCC 22019, C. krusei ATCC 6258, Trichophyton mentagrophytes var. erinacei NCPF 375, Microsporum gypseum NCPF 580, and T. tonsurans NCPF 245. 3c, 3f, 3m, 3n, and 4e showed the highest antibacterial activity. Particularly 3c, 3f, 3g, 3k, 3n, 4a, 4e, and 4g showed the highest antifungal activity against tested fungi.     

Synthesis and Insecticidal Activities of Novel 1,3,4-Thiadiazole 5-Fluorouracil Acetamides Derivatives: An RNA Interference Insecticide

A series of novel 1,3,4-thiadiazole 5-fluorouracil acetamides derivatives were designed and synthesized. Their structures were confirmed by infrared, ¹H NMR spectroscopy, and elemental analysis. The insecticidal activities against Tetranychus cinnabarinus and Aphis craccivora of these new compounds were evaluated. The bioassay tests showed that most of these title compounds possessed a good combination of stomach toxicity as well as contact toxicity against Tetranychus cinnabarinus and Aphis craccivora. In particular, the insecticidal activity of the title compound IVe against Aphis craccivora was better than the commercialized thiacloprid and was also comparable to another commercialized product, imidacloprid. The introduction of fluorines to meta and para-position of the benzene ring was essential for high bioactivity.     

Structure and basicity of 1,2,5-triphenyltriazole-1,3,4 derivatives

The molecular geometry, spectral luminescence properties, proton acceptor ability during the formation of H bonded complexes and monocation formation have been studied for a series of the new near-UV efficient laser dyes: 1,2,5-triphenyltriazole-1,3,4 (TPT) derivatives. It has been shown that the initial proton attachment to TPT molecules is directed to the triazole cycle imine nitrogen atom. The possible reason for the observed abnormally high fluorescence Stokes shifts typical of TPT neutral and cationic forms is discussed. The static mechanism has been demonstrated for TPT fluorescence quenching in acidic media.     

Synthesis,evaluation and in silico molecular modeling of pyrroyl-1,3,4-thiadiazole inhibitors of InhA

Enoyl acyl carrier protein reductase (ENR) is an essential type II fatty acid synthase (FAS-II) pathway enzyme that is an attractive target for designing novel antitubercular agents. Herein, we report sixty-eight novel pyrrolyl substituted aryloxy-1,3,4-thiadiazoles synthesized by three-step optimization processes. Three-dimensional quantitative structure–activity relationships (3D-QSAR) were established for pyrrolyl substituted aryloxy-1,3,4-thiadiazole series of InhA inhibitors using the comparative molecular field analysis (CoMFA). Docking analysis of the crystal structure of ENR performed by using Surflex-Dock in Sybyl-X 2.0 software indicates the occupation of pyrrolyl substituted aryloxy 1,3,4-thiadiazole into hydrophobic pocket of InhA enzyme. Based on docking and database alignment rules, two computational models were established to compare their statistical results. The analysis of 3D contour plots allowed us to investigate the effect of different substituent groups at different positions of the common scaffold. In vitro testing of ligands using biological assays substantiated the efficacy of ligands that were screened through in silico methods.     

Synthesis and antimicrobial activity of new 1,2,4-triazole and 1,3,4-thiadiazole derivatives

In this study, new 3-[(1(2H)-phthalazinone-2-yl(methyl/ethyl]-4-aryl-1,2,4-triazole-5-thione and 2-[[1(2H)-phthalazinone-2-yl]methyl/ethyl]-5-arylamino-1,3,4-thiadiazole derivatives were synthesized. Antimicrobial properties of the title compounds were investigated against two Gram (+) bacteria (S. aureus, B. subtilis), two Gram ( ? ) bacteria (P. aeruginosa, E. coli) and two yeast-like fungi (C. albicans and C. parapsilosis) using the broth microdilution method. Generally the compounds were found to be active against B. subtilis and the fungi. Derivatives carrying a 1,3,4-thiadiazole ring generally showed higher antimicrobial activity against B. subtilis and the fungi when compared to other synthesized compounds.     

Synthesis,structure, and antifungal evaluation of some novel 1,2,4-triazolylmercaptoacetylthiosemicarbazide and 1,2,4-triazolylmercaptomethyl-1,3,4-thiadiazole analogs

Novel 1-[[4-(4-bromophenyl)-5-(2-furyl)-4H-1,2,4-triazole-3-yl]mercaptoacetyl]-4-alkyl/aryl-3-thiosemicarbazides (5–12) were synthesized by the reaction of 4-(4-bromophenyl)-5-(2-furyl)-4H-1,2,4-triazole-3-ylmercaptoacetylhydrazide (4) with substituted isothiocyanates. Cyclodehydration of thiosemicarbazides with concentrated sulfuric acid yielded 2-[4-(4-bromophenyl)-5-(2-furyl)-4H-1,2,4-triazole-3-yl]mercaptomethyl-5-alkyl/arylamino-1,3, 4-thiadiazoles (13–17). The new compounds were evaluated for in vitro antifungal activity using the microdilution method. The tested compounds showed varying degrees of activity against Microsporum gypseum NCPF-580, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, and Candida albicans ATCC 10231 (MIC 8–4 μg/mL).