cas 3004-42-0, 5-(4-METHYLPHENYL)-1,3,4-OXADIAZOLE-2-THIOL

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Synthesis of new 1, 3, 4-oxadiazole-incorporated 1, 2, 3-triazole moieties as potential anticancer agents targeting thymidylate synthase and their docking studies
Thymidylate synthase (TS) has emerged as a hot spot in cancer treatment, as it is directly involved in DNA synthesis. In the present article, nine hybrids containing 1,2,3-triazole and 1,3,4-oxadiazole moieties (6–14) were synthesized and evaluated for anticancer and in vitro thymidylate synthase activities. According to in silico pharmacokinetic studies, the synthesized hybrids exhibited good drug likeness properties and bioavailability. The cytotoxicity results indicated that compounds 12 and 13 exhibited remarkable inhibition on the tested Michigan Cancer Foundation (MCF-7) and Human colorectal Carcinoma (HCT-116) cell lines. Compound 12 showed four-fold inhibition to a standard drug, 5-fluoruracil, and comparable inhibition to tamoxifen, whereas compound 13 exerted five-fold activity of tamoxifen and 24-fold activity of 5-fluorouracil for MCF-7 cells. Compounds 12 and 13 inhibited thymidylate synthase enzyme, with an half maximal inhibitory concentration, IC50 of 2.52 μM and 4.38 μM, while a standard drug, pemetrexed, showed IC50 = 6.75 μM. The molecular docking data of compounds 12 and 13 were found to be in support of biological activities data. In conclusion, hybrids (12 and 13) may inhibit thymidylate synthase enzyme, which could play a significant role as a chemotherapeutic agent.
Alam, Mohammad Mahboob,Almalki, Abdulraheem S. A.,Neamatallah, Thikryat,Ali, Nada M.,Malebari, Azizah M.,Nazreen, Syed
p. 1 - 15
(2020)
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Nickel(II) complexes of 5-phenyl and 5-furan-1,3,4-oxadiazole-2-thiones containing ethylenediamine: Synthesis, spectral and X-ray characterization
The products obtained by the reactions of Ni(OAc)24H 2O with Hpot (Hpot = 5-phenyl-1,3,4-oxadi-azole-2-thione) and [K(H2fchc)] (potassium N'-(furan-2-carbonyl) hydrazine carbodithioate), on treatment with excess of ethylenediamine (en), gave mixed ligand complexes [Ni(pot)2(en)2](1) and [Ni(fot) 2(en)2](2) (fot = 5-furan-(1,3,4)-oxadiazole-2-thione). These complexes have been characterized with the aid of elemental analyses, IR, magnetic susceptibility and single crystal X-ray studies. In both complexes, the heterocyclic ligand coordinates through oxadiazole nitrogen, and the ligand exists as the thione form. The complexes 1 and 2 have distorted octahedral geometries around the centrosymmetric Ni(II) center with trans oxadi-azole ligands. Both complexes show extended hydrogen bonding to give a supramolecular framework. Springer Science+Business Media B.V. 2009.
Singh, Nand K.,Bharty, Manoj K.,Kushawaha, Surendra K.,Butcher, Raymond J.
p. 205 - 211
(2010)
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Efficient formation of C–S bond using heterocyclic thiones and arynes
Phenylthio heterocyclic compounds are widely used because of their diverse biological activities and medicinal prospects. Here, a facile method was reported. An arylation of 1,3,4-oxa(thia)diazol-2-thiones reacting with arynes to build C(aryl)-S bonds in the presence of CsF had good yields and excellent selectivity. The reaction was completed in short time without using expensive reagents and catalysts. Present reaction system is an efficient procedure to process phenylthio heterocyclic compounds and reveals a sustainable method and better application prospects in future organic synthesis.
An, Yu,Xu, Gang,Cai, Menglu,Wang, Shihui,Wang, Xiao zhong,Chen, Yingqi,Dai, Liyan
(2020/12/23)

Pleuromutilin derivative with 1, 3, 4-oxadiazole side chain and preparation and application thereof
The invention belongs to the field of medicinal chemistry, and particularly relates to a pleuromutilin derivative with a 1, 3, 4-oxadiazole side chain and preparation and application thereof The pleuromutilin derivative with the 1, 3, 4-oxadiazole side chain is a compound shown in a formula 2 or a pharmaceutically acceptable salt thereof, and a solvent compound, an enantiomer, a diastereoisomer and a tautomer of the compound shown in the formula 2 or the pharmaceutically acceptable salt thereof or a mixture of the solvent compound, the enantiomer, the diastereoisomer and the tautomer in any proportion, including a racemic mixture. The pleuromutilin derivative has good antibacterial activity, is especially suitable for being used as a novel antibacterial agent for systemic system infection of animals or human beings, and has good water solubility.
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(2021/07/24)

Ultrasound-assisted, low-solvent and acid/base-free synthesis of 5-substituted 1,3,4-oxadiazole-2-thiols as potent antimicrobial and antioxidant agents
Abstract: One of the goals of green chemistry is to use environmentally friendly solvents or remove and reduce the volume of harmful spent solvents. In this study, a novel process for the synthesis of 5-substituted 1,3,4-oxadiazole-2-thiol derivatives was proposed via ultrasound-assisted reaction of aryl hydrazides with CS2 (1:1 molar ratio) in some drops of DMF in the absence of basic or acidic catalysts. They were produced in good to excellent yields under easy workup and purification conditions. In order to prove the usefulness of the prepared compounds, their antioxidant, antibacterial, and antifungal potentials were screened by DPPH free radical scavenging, serial twofold microdilution and streak plate methods. Acceptable to significant inhibitory activities were observed with synthesized heterocycles. The results showed that 5-(4-fluorophenyl)-1,3,4-oxadiazole-2-thiol (3c) is an broad-spectrum antimicrobial agent. Many of them displayed remarkable antioxidant properties comparable to standard controls (ascorbic acid and α-tocopherol). Synthesized 1,3,4-oxadiazoles are also potent candidates to treat cancer, Parkinson, inflammatory, and diabetes diseases. Graphic Abstract: Eighteen 5-substituted 1,3,4-oxadiazole-2-thiol derivatives as potent antimicrobial and antioxidant agents were prepared via a new, efficient and green procedure.[Figure not available: see fulltext.].
Yarmohammadi, Elahe,Beyzaei, Hamid,Aryan, Reza,Moradi, Ashraf
p. 2367 - 2378
(2020/08/10)

Design, synthesis, in vitro and in vivo evaluation against MRSA and molecular docking studies of novel pleuromutilin derivatives bearing 1, 3, 4-oxadiazole linker
A class of pleuromutilin derivatives containing 1, 3, 4-oxadiazole were designed and synthesized as potential antibacterial agents against Methicillin-resistant staphylococcus aureus (MRSA). The ultrasound-assisted reaction was proposed as a green chemistry method to synthesize 1, 3, 4-oxadiazole derivatives (intermediates 85–110). Among these pleuromutilin derivatives, compound 133 was found to be the strongest antibacterial derivative against MRSA (MIC = 0.125 μg/mL). Furthermore, the result of the time-kill curves displayed that compound 133 could inhibit the growth of MRSA in vitro quickly (- 4.36 log10 CFU/mL reduction). Then, compound 133 (- 1.82 log10 CFU/mL) displayed superior in vivo antibacterial efficacy than tiamulin (- 0.82 log10 CFU/mL) in reducing MRSA load in mice thigh model. Besides, compound 133 exhibited low cytotoxicity to RAW 264.7 cells. Molecular docking studies revealed that compound 133 was successfully localized in the binding pocket of 50S ribosomal subunit (ΔGb = -10.50 kcal/mol). The results indicated that these pleuromutilin derivatives containing 1, 3, 4-oxadiazole might be further developed into novel antibiotics against MRSA.
Liu, Jie,Zhang, Guang-Yu,Zhang, Zhe,Li, Bo,Chai, Fei,Wang, Qi,Zhou, Zi-Dan,Xu, Ling-Ling,Wang, Shou-Kai,Jin, Zhen,Tang, You-Zhi
(2021/05/17)

Novel 1,3,4-oxadiazole compounds inhibit the tyrosinase and melanin level: Synthesis, in-vitro, and in-silico studies
In this research work, we have designed and synthesized some biologically useful of 1,3,4-Oxadiazoles. The structural interpretation of the synthesized compounds has been validated by using FT-IR, LC-MS, HRMS, 1H NMR and 13C NMR techniques. Moreover, the in-vitro mushroom tyrosinase inhibitory potential of the target compounds was assessed. The in-vitro study reveals that, all compounds demonstrate an excellent tyrosinase inhibitory activity. Especially, 2-(5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-ylthio)-N-phenylacetamide (IC50 = 0.003 ± 0.00 μM) confirms much more significant potent inhibition activity compared with standard drug kojic acid (IC50 = 16.83 ± 1.16 μM). Subsequently, the most potent five oxadiazole compounds were screened for cytotoxicity study against B16F10 melanoma cells using an MTT assay method. The survival rate for the most potent compound was more pleasant than other compounds. Furthermore, the western blot results proved that the most potent compound considerably decreased the expression level of tyrosinase at 50 μM (P 0.05). The molecular docking investigation exposed that the utmost potent compound displayed the significant interactions pattern within the active region of the tyrosinase enzyme and which might be responsible for the decent inhibitory activity towards the enzyme. A molecular dynamic simulation experiment was presented to recognize the residual backbone stability of protein structure.
Vanjare, Balasaheb D.,Choi, Nam Gyu,Mahajan, Prasad G.,Raza, Hussain,Hassan, Mubashir,Han, Yohan,Yu, Seon-Mi,Kim, Song Ja,Seo, Sung-Yum,Lee, Ki Hwan
(2021/06/07)

Antibacterial and Antiviral Activities of 1,3,4-Oxadiazole Thioether 4H-Chromen-4-one Derivatives
Various 1,3,4-oxadiazole thioether 4H-chromen-4-one derivatives were conceived. The title compounds demonstrated striking inhibitory effects againstXac,Psa, andXoo. EC50data exhibited that A8 (19.7 μg/mL) had better antibacterial activity againstXoothan myricetin, BT, and TC. Simultaneously, the mechanism of action of A8 had been verified by SEM. The results of anti-tobacco mosaic virus indicated that A9 had the bestin vivoantiviral effect compared with ningnanmycin. From the data of MST, it could be seen that A9 (0.003 ± 0.001 μmol/L) exhibited a strong binding capacity, which was far superior to ningnanmycin (2.726 ± 1.301 μmol/L). This study shows that the 1,3,4-oxadiazole thioether 4H-chromen-4-one derivatives may become agricultural drugs with great potential.
Cao, Xiao,Liu, Fang,Liu, Liwei,Liu, Tingting,Peng, Feng,Wang, Qifan,Xie, Chengwei,Xue, Wei,Yang, Jinsong
p. 11085 - 11094
(2021/10/01)

Development of Novel (+)-Nootkatone Thioethers Containing 1,3,4-Oxadiazole/Thiadiazole Moieties as Insecticide Candidates against Three Species of Insect Pests
To improve the insecticidal activity of (+)-nootkatone, a series of 42 (+)-nootkatone thioethers containing 1,3,4-oxadiazole/thiadiazole moieties were prepared to evaluate their insecticidal activities against Mythimna separata Walker, Myzus persicae Sulzer, and Plutella xylostella Linnaeus. Insecticidal evaluation revealed that most of the title derivatives exhibited more potent insecticidal activities than the precursor (+)-nootkatone after the introduction of 1,3,4-oxadiazole/thiadiazole on (+)-nootkatone. Among all of the (+)-nootkatone derivatives, compound 8c (1 mg/mL) exhibited the best growth inhibitory (GI) activity against M. separata with a final corrected mortality rate (CMR) of 71.4%, which was 1.54- and 1.43-fold that of (+)-nootkatone and toosendanin, respectively; 8c also displayed the most potent aphicidal activity against M. persicae with an LD50 value of 0.030 μg/larvae, which was closer to that of the commercial insecticidal etoxazole (0.026 μg/larvae); and 8s showed the best larvicidal activity against P. xylostella with an LC50 value of 0.27 mg/mL, which was 3.37-fold that of toosendanin and slightly higher than that of etoxazole (0.28 mg/mL). Furthermore, the control efficacy of 8s against P. xylostella in the pot experiments under greenhouse conditions was better than that of etoxazole. Structure-activity relationships (SARs) revealed that in most cases, the introduction of 1,3,4-oxadiazole/thiadiazole containing halophenyl groups at the C-13 position of (+)-nootkatone could obtain more active derivatives against M. separata, M. persicae, and P. xylostella than those containing other groups. In addition, toxicity assays indicated that these (+)-nootkatone derivatives had good selectivity to insects over nontarget organisms (normal mammalian NRK-52E cells and C. idella and N. denticulata fries) with relatively low toxicity. Therefore, the above results indicate that these (+)-nootkatone derivatives could be further explored as new lead compounds for the development of potential eco-friendly pesticides.
Cheng, Wanqing,Fan, Jiangping,Guo, Yong,Han, Meiyue,Ma, Nannan,Yan, Xiaoting,Yang, Ruige
p. 15544 - 15553
(2022/01/03)

Synthesis and Biological Evaluation of Oxadiazole Clubbed Thiadiazole Derivatives as Antimicrobial Agents
A series of 1,3,4-oxadiazole clubbed 1,3,4-thiadiazole derivatives were synthesized and assessed in vitro for their activity as antimicrobial agents. The target compounds 2-(5-(substituted aryl)-1, 3, 4-oxadiazol-2-ylthio)-N-(5-(substituted aryl)-1, 3, 4-thiadiazol-2-yl) acetamides (5a-5s) were synthesized using a basic condensation reaction between 5-(substituted aryl)-1,3,4-oxadiazole-2-thiol and 2-chloro-N-(5-(substituted aryl)-1,3,4-thiadiazol-2-yl)acetamide in presence of K2CO3 as a scavenging agent and acetone as reaction solvent. The titled compounds synthesized here, exhibited excellent to moderate antimicrobial activity against a broad panel of antibacterial strains of Gram-positive and Gram-negative bacteria and fungi.
Begari, Eeshwaraiah,Dave, Alpa Y.,Joshi, Deepkumar S.,Parmar, Kokila A.
p. 273 - 280
(2021/08/03)

Design, synthesis and biological evaluation of triazole-oxadiazole conjugates for the management of cognitive dysfunction
Acetylcholinesterase has been a promising target for the development of putative therapeutics against cognitive decline. The deleterious effect of oxidative stress on the learning and memory paradigms of an individual has also been well documented. In view of this, the present study demonstrates the design, synthesis and pharmacological evaluation of triazole-oxadiazole conjugates. Eighteen novel hybrids (6–23) have been synthesised by employing suitable synthetic procedures and characterized by various spectral and elemental techniques. Further these synthesised compounds were evaluated against behavioural alterations using step down passive avoidance and escape learning protocol at a dose of 0.5 mg/kg with reference to the standard, donepezil. All the synthesised compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibition at five different concentrations using mice brain homogenate as the source of the enzyme. Biochemical estimation of markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione and catalase) has also been carried out to assess the role of synthesised molecules on the oxidative damage induced by scopolamine. The compounds 13, 17 and 23 displayed appreciable activity towards acetylcholinesterase inhibition. These compounds also decreased scopolamine induced oxidative stress, thus serving as promising leads for the amelioration of oxidative stress induced cognitive decline. The molecular docking study performed to predict the binding mode of the compounds also suggested that these compounds bind appreciably to the amino acids present in the active site of the recombinant human acetylcholinesterase (rhAChE). The results indicated that these compounds could be further traversed as inhibitors of AChE and oxidative stress for the treatment of cognitive dysfunction.
Jain, Ankit,Piplani, Poonam
(2020/09/01)

Synthesis, antifungal and antibacterial activity of calix[4]arene-based 1,3,4-oxadiazole derivatives
We describe the synthesis of some novel p-tert-butylcalix[4]arene-based (5-aryl-1,3,4-oxadiazol-2-yl)2-chloroethanethioate derivatives (4a–e). These compounds were synthesized by the reaction of tetra-tert-butyl calix[4]arene (1) with (5-aryl-1,3,4-oxadiazol-2-yl)2-chloroethanethioate (3a–e) in the presence of potassium carbonate as a weak base and dry acetone as the solvent. All the newly synthesized calix[4]arene derivatives were characterized by elemental analysis and various spectroscopic methods such as FT-IR, 1H NMR,13C NMR, DEPT, and ESI-MS. The synthesized compounds were tested in vitro for their antibacterial and antifungal activities against Escherichia coli and Aspergillus fumigates in comparison with enrofloxacin and amphotericin as reference drugs, which are normally used for treating such infections. The synthesized compounds showed different inhibition zones against the tested bacteria and fungi. Compound 4c was found to be most effective against A. fumigates, whereas compound 4e was found to be equally effective against E. coli and A. fumigates.
Dono Gezelbash, Zahra,Akbari Dilmaghani, Karim
p. 1446 - 1452
(2020/03/11)

4-Amino-1,2,4-triazole-3-thione-derived Schiff bases as metallo-β-lactamase inhibitors
Resistance to β-lactam antibiotics in Gram-negatives producing metallo-β-lactamases (MBLs) represents a major medical threat and there is an extremely urgent need to develop clinically useful inhibitors. We previously reported the original binding mode of 5-substituted-4-amino/H-1,2,4-triazole-3-thione compounds in the catalytic site of an MBL. Moreover, we showed that, although moderately potent, they represented a promising basis for the development of broad-spectrum MBL inhibitors. Here, we synthesized and characterized a large number of 4-amino-1,2,4-triazole-3-thione-derived Schiff bases. Compared to the previous series, the presence of an aryl moiety at position 4 afforded an average 10-fold increase in potency. Among 90 synthetic compounds, more than half inhibited at least one of the six tested MBLs (L1, VIM-4, VIM-2, NDM-1, IMP-1, CphA) with Ki values in the μM to sub-μM range. Several were broad-spectrum inhibitors, also inhibiting the most clinically relevant VIM-2 and NDM-1. Active compounds generally contained halogenated, bicyclic aryl or phenolic moieties at position 5, and one substituent among o-benzoic, 2,4-dihydroxyphenyl, p-benzyloxyphenyl or 3-(m-benzoyl)-phenyl at position 4. The crystallographic structure of VIM-2 in complex with an inhibitor showed the expected binding between the triazole-thione moiety and the dinuclear centre and also revealed a network of interactions involving Phe61, Tyr67, Trp87 and the conserved Asn233. Microbiological analysis suggested that the potentiation activity of the compounds was limited by poor outer membrane penetration or efflux. This was supported by the ability of one compound to restore the susceptibility of an NDM-1-producing E. coli clinical strain toward several β-lactams in the presence only of a sub-inhibitory concentration of colistin, a permeabilizing agent. Finally, some compounds were tested against the structurally similar di-zinc human glyoxalase II and found weaker inhibitors of the latter enzyme, thus showing a promising selectivity towards MBLs.
Baud, Damien,Bebrone, Carine,Becker, Katja,Benvenuti, Manuela,Cerboni, Giulia,Chelini, Giulia,Cutolo, Giuliano,De Luca, Filomena,Docquier, Jean-Denis,Feller, Georges,Fischer, Marina,Galleni, Moreno,Gavara, Laurent,Gresh, Nohad,Kwapien, Karolina,Legru, Alice,Mangani, Stefano,Mercuri, Paola,Pozzi, Cecilia,Sannio, Filomena,Sevaille, Laurent,Tanfoni, Silvia,Verdirosa, Federica,Berthomieu, Dorothée,Bestgen, Beno?t,Frère, Jean-Marie,Hernandez, Jean-Fran?ois
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(2020/09/16)

Design, synthesis, and in vitro evaluation of novel 1,3,4-oxadiazolecarbamothioate derivatives of Rivastigmine as selective inhibitors of BuChE
Rivastigmine has been prescribed for the therapy of Alzheimer’s disease (AD) symptoms. This drug is classified in the carbamate derivative group that has dual activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). According to the structure of Rivastigmine and its performance, a new series of 5-aryl-1,3,4-oxadiazole-2-carbamothioate compounds I–XI was synthesized using structure-based drug discovery approaches. For this purpose a set of these compounds were designed with computational docking method and their interactions with amino acid residues in the active sites of AChE and BuChE checked out. The structures of synthesized compounds were established by physicochemical and spectroscopic methods. The carbamoyl moiety of Rivastigmine structure was modified to carbamothioate and the effects of 1,3,4-oxadiazole heterocycle as a pharmacophoric nucleus were investigated. The potential of the synthesized compounds I–XI was evaluated against two most known agents of AD (AChE and BuChE) to determine their IC50 values. The results of the docking showed the range of binding affinity for the best poses of ten individual conformers for any compounds (I–XI) was between ?7.81 (VI) and ?6.75 (II) kcal/mol. The results of biological experiments displayed that most synthetic compounds (I–VIII) showed moderate to excellent selective activity range against BuChE (0.51–69.44 μM). In vitro cytotoxicity evaluation of these compounds (I–XI) by MTT assay on human dermal fibroblast (HDF) cell line exhibited no activity against HDF. The compound VI [S-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl) ethyl(methyl)carbamothioate] showed the most stable binding affinity (?7.81 kcal/mol) and the lowest IC50 value (0.51 μM) in comparison with Rivastigmine with 7.72 μM and Donepezil with 5.20 μM against BuChE.
Fallah, Akram,Mohanazadeh, Farajollah,Safavi, Maliheh
p. 341 - 355
(2019/12/30)

Synthetic and theoretical investigation on nano-Au/TiO2 catalyzed hydrothiolation for construction of C─S bond: Experimental and DFT study
In this article, we describe a new synthetic and theoretical approach for the construction of C─S bond in heterocyclic molecules undergoing nanogold catalytic hydrothiolation reaction. The experimental studies showed that the reaction proceeded via regioselective Michael-type anti-addition and gave the corresponding sulfur bridged 1,3,4-oxadiazole-propenone in excellent yield. The compounds were characterized by analytical and spectral techniques. A gas phase molecular modeling study of nanogold-catalyzed hydrothiolation of acetylenic ketone with 5-aryl-1,3,4-oxadiazol-2-thiol was carried out using density functional theory (DFT) calculations. It showed the adsorption of acetylenic ketone on nanogold and preferable coordination at the β carbon of the alkyne group. The charge calculations showed that on adsorption over nanogold, the alkyne group became more polar in nature. The frontier highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) analysis showed a possible overlap of molecular orbitals between thiol and acetylenic β carbon to give Z isomer. The experimental and theoretical validation of bond parameters was carried out. A possible mechanism of hydrothiolation reaction was proposed based on the analogy with the results of theoretical calculations and experimental evidence.
Turukarabettu, Vishwanath,Kalluraya, Balakrishna
supporting information

(2019/12/15)

Design and synthesis of quinoxaline-1,3,4-oxadiazole hybrid derivatives as potent inhibitors of the anti-apoptotic Bcl-2 protein
Quinoxaline is one of the privileged heterocyclic fragments for drug molecules. Quinoxaline anticancer drug candidates XK469 and CQS exhibit antiproliferative and proapoptotic properties against various cancers. Based on their chemical structures, we therefore synthesized a series of quinoxaline-1,3,4-oxadiazole hybrids and assessed their anticancer potential on human leukemia HL-60 cells. Although these hybrids exerted significant inhibition of HL-60 cell proliferation, they showed high cytotoxicity on human normal cells (WI-38). Utilizing information from molecular modelling of the hybrids to the anti-apoptotic Bcl-2 protein, we added substructures including phenyl, piperazine, piperidine, and morpholine rings to their frameworks. The designed quinoxaline-1,3,4-oxadiazole hybrid derivatives successfully induced apoptotic response on HL-60 cells with low toxicity on WI-38 cells. Furthermore, RT-PCR analysis demonstrated that these derivatives predominantly inhibit Bcl-2 expression. Our findings highlight the great potential for the development of synthetic quinoxaline-1,3,4-oxadiazole hybrid derivatives as proapoptotic anticancer agents.
Ono, Yukari,Ninomiya, Masayuki,Kaneko, Daiki,Sonawane, Amol D.,Udagawa, Taro,Tanaka, Kaori,Nishina, Atsuyoshi,Koketsu, Mamoru
(2020/09/09)

Synthesis of [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-oxadiazole derivatives as potent antiproliferative agents via a hybrid pharmacophore approach
Imiquimod (1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine) is efficacious in topical therapy for certain types of skin cancers. Structurally similar EAPB0203 (N-methyl-1-(2-phenethyl)imidazo[1,2-a]quinoxalin-4-amine) has been shown higher in vitro potency than imiquimod. Besides, triazole, oxadiazole, and thiadiazole rings are privileged building blocks in drug design. A series of [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-oxadiazole and [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-thiadiazole derivatives were therefore synthesized by incorporation of these rings into the structure of EAPB0203 and assessed their antiproliferative effects against various cancer cell lines. The 1,3,4-oxadiazole derivatives demonstrated the superior effectiveness compared to imiquimod and EAPB0203. Our findings highlight the excellent potential of [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-oxadiazole derivatives as anticancer agents.
Kaneko, Daiki,Ninomiya, Masayuki,Yoshikawa, Rina,Ono, Yukari,Sonawane, Amol D.,Tanaka, Kaori,Nishina, Atsuyoshi,Koketsu, Mamoru
(2020/10/06)

Design, synthesis, and biological evaluation of new challenging thalidomide analogs as potential anticancer immunomodulatory agents
Thalidomide and its analogs are immunomodulatory drugs that inhibit the production of certain inflammatory mediators associated with cancer. In the present work, a new series of thalidomide analogs was designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against a panel of four cancer cell lines (HepG-2, HCT-116, PC3 and MCF-7). Compounds 33h, 33i, 42f and 42h showed strong potencies against all tested cell lines with IC50 values ranging from 14.63 to 49.90 μM comparable to that of thalidomide (IC50 values ranging from 32.12 to 76.91 μM). The most active compounds were further evaluated for their in vitro immunomodulatory activities via estimation of human tumor necrosis factor alpha (TNF-α), human caspase-8 (CASP8), human vascular endothelial growth factor (VEGF), and nuclear factor kappa-B P65 (NF-κB P65) in HCT-116 cells. Thalidomide was used as a positive control. Compounds 33h and 42f showed a significant reduction in TNF-α. Furthermore, compounds 33i and 42f exhibited significant elevation in CASP8 levels. Compounds 33i and 42f inhibited VEGF. In addition, compound 42f showed significant decrease in levels of NF-κB p65. Moreover, apoptosis and cell cycle tests of the most active compound 42f, were performed. The results indicated that compound 42f significantly induce apoptosis in HCT-116 cells and arrest cell cycle at the G2/M phase.
El-Zahabi, Mohamed Ayman,Sakr, Helmy,El-Adl, Khaled.,Zayed, Mohamed,Abdelraheem, Adel S.,Eissa, Sally I.,Elkady, Hazem,Eissa, Ibrahim H.
(2020/09/16)

Synthesis and Characterization of New Ligand N,N-Dimethyl-4-[(E)-(2-{5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)hydrazinyl]-1,3,4-thiadiazol-2-cyl}hydrazinylidene) methyl]aniline and Transition Metal Complexes
A new ligand N,N-dimethyl-4-((2-(5-(2-(5-phenyl-1,3,4-oxadiazole-2-yl)hydrazinyl)-1,3,4-thiadiazol-2-yl)hydrazono)methyl)aniline and its Cr(III),Ni(II) and Co(II) complexes were synthesized, and characterized by FTIR, 1H-NMR, and mass spectral data. The ligand acts as bidentate ligand coordinating through the nitrogen atom. The program of hyperchem 8 has been used for theoretical accounts using PM3 method to study the electrostatic potential that provided good information to determine the appropriate positioning complexity. Based on the spectral data, the octahedral geometry for the Cr(III), tetrahedral geometry for Co(II), and square planar geometry for Ni (II) have been suggested.
Nasir, Ali.F.,Flifl, Ibrahim A.
p. 453 - 457
(2021/02/02)

1,3,4-oxadiazole/chalcone hybrids: Design, synthesis, and inhibition of leukemia cell growth and EGFR, Src, IL-6 and STAT3 activities
A new series of 1,3,4-oxadiazole/chalcone hybrids was designed, synthesized, identified with different spectroscopic techniques and biologically evaluated as inhibitors of EGFR, Src, and IL-6. The synthesized compounds showed promising anticancer activity, particularly against leukemia, with 8v being the most potent. The synthesized compounds exhibited strong to moderate cytotoxic activities against K-562, KG-1a, and Jurkat leukemia cell lines in MTT assays. Compound 8v showed the strongest cytotoxic activity with IC50 of 1.95 μM, 2.36 μM and 3.45 μM against K-562, Jurkat and KG-1a leukemia cell lines, respectively. Moreover; the synthesized compounds inhibited EGFR, Src, and IL-6. Compound 8v was most effective at inhibiting EGFR (IC50 = 0.24 μM), Src (IC50 = 0.96 μM), and IL-6 (% of control = 20%). Additionally, most of the compounds decreased STAT3 activation.
Fathi, Marwa Ali A.,Abd El-Hafeez, Amer Ali,Abdelhamid, Dalia,Abbas, Samar H.,Montano, Monica M.,Abdel-Aziz, Mohamed
p. 150 - 163
(2018/12/11)

Synthesis, characterization, and nonlinear optical properties of some new series of S-(5-aryl-1,3,4-oxadiazol-2-yl) 2-chloroethanethioate derivatives
In the present investigation, some novel S-(5-aryl-1,3,4-oxadiazol-2-yl)2-chloroethanethioate (3a–3e) derivatives were synthesized and their impact on optical properties was studied. They have also been characterized by elemental analysis and various spectroscopic methods including FTIR, 1 H NMR, 13 C NMR, and UV-Vis techniques. The nonlinear refractive indexes of 3a–3e were also measured in dichloromethane via Z-scan method using a continuous wave diode-pumped laser at 532 nm wavelength. The nonlinear refractive coefficient of compounds was obtained from 1011 m2/W order. Regarding the appropriate nonlinearity of these compounds, they could be considered good candidates for biooptical and photonic applications. All the synthesized compounds (3a–3e) have also been evaluated for their antimicrobial and antifungal activities. The bioactive assay showed that the synthetic compounds displayed variable inhibition zones against tested bacterium Escherichia coli and fungus Aspergillus fumigatus in comparison to enrofloxacin and amphotericin as reference drugs, which are normally used for treating such infections.
Ghezelbash, Zahra Dono,Motiei, Hamideh,Mahmoody, Miri,Dilmaghani, Karim Akbari
p. 902 - 910
(2019/07/17)

DMF as Methine Source: Copper-Catalyzed Direct Annulation of Hydrazides to 1,3,4-Oxadiazoles
An unprecedented Cu-catalyzed direct annulation of hydrazides with N,N-dimethylformamide (DMF) was developed, providing an efficient synthesis of valuable 1,3,4-oxadiazoles. This process features the short reaction time and can be safely conducted on gram scale. The reaction also facilitated the convenient synthesis of 1,3,4-oxadiazole-2(3H)-ones. Moreover, the mechanistic studies suggest that the source of CH is from the N-methyl group of DMF. (Figure presented.).
Wang, Shoucai,Wang, Kai,Kong, Xiangfei,Zhang, Shuhua,Jiang, Guangbin,Ji, Fanghua
p. 3986 - 3990
(2019/07/31)

Synthesis, molecular docking, antimicrobial evaluation, and DNA cleavage assay of new thiadiazole/oxadiazole ciprofloxacin derivatives
Abstract: Herein we report the synthesis of new N-4-piperazinyl thiadiazole and oxadiazole ciprofloxacin derivatives and their antibacterial and antimycobacterial activities. Although thiadiazole ciprofloxacin derivatives compound showed broad spectrum antibacterial activity against all the tested strains either Gram-positive or Gram-negative organisms, the oxadiazole derivatives exhibited weaker antibacterial and antimycobacterial activities than thiadiazole derivatives against most of the tested strains compared with the reference ciprofloxacin. Moreover, the antimycobacterial screening revealed that compounds which containing thiadiazole scaffold potently inhibited Mycobacterium smegmatis at MIC of 1.56 and 3.13, respectively, and modestly inhibited the drug-resistant strains. DNA cleavage assay revealed that thiadiazole ciprofloxacin derivatives inhibited supercoil relaxation, albeit to a lesser extent than ciprofloxacin, and it also increased the amount of nicked substrate produced. Graphic abstract: [Figure not available: see fulltext.].
Mohammed, Hamada H. H.,Abbas, Samar H.,Abdelhafez, El-Shimaa M. N.,Berger, James M.,Mitarai, Satoshi,Arai, Masayoshi,Abuo-Rahma, Gamal El-Din A. A.
p. 1809 - 1824
(2019/11/05)

Synthesis and anticancer evaluation of new lipophilic 1,2,4 and 1,3,4-oxadiazoles
A series of1,2,4- and 1,3,4-oxadiazole derivatives were synthesized and evaluated for their anticancer activity. Halogenated 1,2,4-oxadiazoles were obtained from benzonitrile and coupled either lipophilic amines or with aminoalcohols. Lipophilic 1,3,4-oxadiazole derivatives were obtained through the Mannich reactions between 5-(aryl)-1,3,4-oxadiazole-2-thiol and alkylated or acylated amines. The in vitro cytotoxic effects were evaluated against 4T1– mammary carcinoma and CT26 – colon cancer cells. The best results were obtained for the 1,3,4-oxadiazole coupled to alkylated piperazine with 10–14 carbon chain moiety, with IC50 values ranging from 1.6 to 3.55μΜ for the 4T1 cell line, and from 1.6 to 3.9 μM for the CT26.WT cell line, and selectivity index up to 19. The most potent compounds were investigated with AnnexinV and PI staining as indicative of apoptosis induction.
Caneschi, Wiliam,Enes, Karine Braga,Carvalho de Mendon?a, Camille,de Souza Fernandes, Fábio,Miguel, Fabio Balbino,da Silva Martins, Jefferson,Le Hyaric, Mireille,Pinho, Roberto Rosas,Duarte, Lucas Mattos,Leal de Oliveira, Marcone Augusto,Dos Santos, Hélio F.,Paz Lopes, Miriam Teresa,Dittz, Dalton,Silva, Heveline,Costa Couri, Mara Rubia
p. 18 - 30
(2019/01/16)

Synthesis of novel indole derivatives containing double 1,3,4-oxadiazole moiety as efficient bactericides against phytopathogenic bacterium Xanthomonas oryzae
Abstract: A series of novel indole derivatives containing double 1,3,4-oxadiazole moiety was designed, synthesized and evaluated for their antibacterial activities in vitro. These compounds were fully characterized by 1H NMR, 13C NMR, and HRMS. Bioassay results indicated that most of title compounds exhibited excellent antibacterial activities against rice bacterial pathogen Xanthomonas oryzae (Xoo). For example, compounds 7d, 7h, 7i, 7j, 7k, 7l and 7m had the half-maximal effective concentration (EC50) values of 52.31, 54.12, 40.65, 38.80, 51.13, 52.75 and 50.66?μg/mL, respectively, which was better than that of commercial product bismerthiazol (BMT) (85.18?μg/mL). The experimental results proved that indole derivatives bearing double 1,3,4-oxadiazole unit are promising candidates for the development of new agricultural bactericides against pathogenic bacterium Xoo. Graphical abstract: [Figure not available: see fulltext.].
Tian, Kun,Li, Xiao-Qin,Zhang, Li,Gan, Yi-Yuan,Meng, Jiao,Wu, Shou-Qun,Wan, Jin-Lin,Xu, Yang,Cai, Chao-Ting,Ouyang, Gui-Ping,Wang, Zhen-Chao
p. 17 - 25
(2019/02/12)

Rational Optimization and Action Mechanism of Novel Imidazole (or Imidazolium)-Labeled 1,3,4-Oxadiazole Thioethers as Promising Antibacterial Agents against Plant Bacterial Diseases
The emergence and widespread occurrence of plant bacterial diseases that cause global production constraints have become major challenges to agriculture worldwide. To promote the discovery and development of new bactericides, imidazole-labeled 1,3,4-oxadiazole thioethers were first fabricated by integrating the crucially bioactive scaffolds of the imidazole motif and 1,3,4-oxadiazole skeleton in a single molecular architecture. Subsequently, a superior antibacterial compound A6 was gradually discovered possessing excellent competence against plant pathogens Xanthomonas oryzae pv oryzae and Xanthomonas axonopodis pv citri with EC50 values of 0.734 and 1.79 μg/mL, respectively. These values were better than those of commercial agents bismerthiazol (92.6 μg/mL) and thiodiazole copper (77.0 μg/mL). Further modifying the imidazole moiety into the imidazolium scaffold led to the discovery of an array of potent antibacterial compounds providing the corresponding minimum EC50 values of 0.295 and 0.607 μg/mL against the two strains. Moreover, a plausible action mechanism for attacking pathogens was proposed based on the concentration dependence of scanning electron microscopy, transmission electron microscopy, and fluorescence microscopy images. Given the simple molecular structures, easy synthetic procedure, and highly efficient bioactivity, imidazole (or imidazolium)-labeled 1,3,4-oxadiazole thioethers can be further explored and developed as promising indicators for the development of commercial drugs.
Wang, Pei-Yi,Wang, Ming-Wei,Zeng, Dan,Xiang, Meng,Rao, Jia-Rui,Liu, Qing-Qing,Liu, Li-Wei,Wu, Zhi-Bing,Li, Zhong,Song, Bao-An,Yang, Song
p. 3535 - 3545
(2019/03/26)

5-Aryl-1,3,4-oxadiazol-2-ylthioalkanoic Acids: A Highly Potent New Class of Inhibitors of Rho/Myocardin-Related Transcription Factor (MRTF)/Serum Response Factor (SRF)-Mediated Gene Transcription as Potential Antifibrotic Agents for Scleroderma
Through a phenotypic high-throughput screen using a serum response element luciferase promoter, we identified a novel 5-aryl-1,3,4-oxadiazol-2-ylthiopropionic acid lead inhibitor of Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF)-mediated gene transcription with good potency (IC50 = 180 nM). We were able to rapidly improve the cellular potency by 5 orders of magnitude guided by sharply defined and synergistic SAR. The remarkable potency and depth of the SAR, as well as the relatively low molecular weight of the series, suggests, but does not prove, that binding to the unknown molecular target may be occurring through a covalent mechanism. The series nevertheless has no observable cytotoxicity up to 100 μM. Ensuing pharmacokinetic optimization resulted in the development of two potent and orally bioavailable anti-fibrotic agents that were capable of dose-dependently reducing connective tissue growth factor gene expression in vitro as well as significantly reducing the development of bleomycin-induced dermal fibrosis in mice in vivo.
Kahl, Dylan J.,Hutchings, Kim M.,Lisabeth, Erika Mathes,Haak, Andrew J.,Leipprandt, Jeffrey R.,Dexheimer, Thomas,Khanna, Dinesh,Tsou, Pei-Suen,Campbell, Phillip L.,Fox, David A.,Wen, Bo,Sun, Duxin,Bailie, Marc,Neubig, Richard R.,Larsen, Scott D.
p. 4350 - 4369
(2019/05/08)

Synthesis and bioactivity of sulfide derivatives containing 1,3,4-oxadiazole and pyridine
A series of novel sulfide derivatives containing 1,3,4-oxadiazole and pyridine were synthesized, characterized, and tested for their antibacterial activity against tobacco bacterial wilt and rice bacterial blight and for insecticidal activity toward diamondback moth. The results showed that some compounds had good insecticidal and bactericidal activity, e.g., the activities of compounds 6e and 6g–6j toward tobacco bacterial wilt were much better than those of commercial thiodiazole-copper, and some of the synthesized compounds possessed good insecticidal activity against Plutella xylostella. Compounds 6d, 6h, 6j, 6l, 6p, 6r, and 6p displayed over 93% activity at 500 mg L? 1.
Yu, Gang,Chen, Shunhong,He, Feng,Luo, Dexia,Zhang, Yu,Wu, Jian
p. 1075 - 1085
(2019/09/10)

Design, synthesis, in-vitro thymidine phosphorylase inhibition, in-vivo antiangiogenic and in-silico studies of C-6 substituted dihydropyrimidines
Thymidine phosphorylase (TP) is an angiogenic enzyme. It plays an important role in angiogenesis, tumour growth, invasion and metastasis. In current research work, we study the effect of structural modification of dihydropyrimidine-2-ones (DHPM-2-ones) on TP inhibition. A series of eighteen new derivatives of 3,4-dihydropyrimidone-2-one were designed and synthesized through the structural modification at C-6 position. All these new derivatives were then assessed for in-vitro inhibition of thymidine phosphorylase (TP) from E. coli. Oxadiazole derivatives 4a-e exhibited excellent TP-inhibition at low micromolar concentration levels better than standard drug 7-deazaxanthine (7-DX). Among all these compounds, 4b was found to be the most potent with IC50 = 1.09 ± 0.004 μM. Anti-angiogenesis potential of representative compounds were also studied in a chorioallantoic membrane (CAM) assay. Here again, compound 4b was found to be the potent anti-angiogenesis compound in a CAM assay. Docking studies were also performed with Molecular Operating Environment (MOE) to further analyse the mode of inhibition of these compounds. Binding mode analysis of the most active inhibitors showed that these are well accommodated into the binding site of enzyme though stable hydrogen bonding and hydrophobic interactions.
Iftikhar, Fatima,Yaqoob, Farhana,Tabassum, Nida,Jan, Muhammad Saeed,Sadiq, Abdul,Tahir, Saba,Batool, Tahira,Niaz, Basit,Ansari, Farzana Latif,Choudhary, Muhammad Iqbal,Rashid, Umer
p. 99 - 111
(2018/06/12)

Antifungal benzo[b]thiophene 1,1-dioxide IMPDH inhibitors exhibit pan-assay interference (PAINS) profiles
Fungi cause serious life-threatening infections in immunocompromised individuals and current treatments are now complicated by toxicity issues and the emergence of drug resistant strains. Consequently, there is a need for development of new antifungal drugs. Inosine monophosphate dehydrogenase (IMPDH), a key component of the de novo purine biosynthetic pathway, is essential for growth and virulence of fungi and is a potential drug target. In this study, a high-throughput screen of 114,000 drug-like compounds against Cryptococcus neoformans IMPDH was performed. We identified three 3-((5-substituted)-1,3,4-oxadiazol-2-yl)thio benzo[b]thiophene 1,1-dioxides that inhibited Cryptococcus IMPDH and also possessed whole cell antifungal activity. Analogs were synthesized to explore the SAR of these hits. Modification of the fifth substituent on the 1,3,4-oxadiazole ring yielded compounds with nanomolar in vitro activity, but with associated cytotoxicity. In contrast, two analogs generated by substituting the 1,3,4-oxadiazole ring with imidazole and 1,2,4-triazole gave reduced IMPDH inhibition in vitro, but were not cytotoxic. During enzyme kinetic studies in the presence of DTT, nucleophilic attack of a free thiol occurred with the benzo[b]thiophene 1,1-dioxide. Two representative compounds with substitution at the 5 position of the 1,3,4-oxadiazole ring, showed mixed inhibition in the absence of DTT. Incubation of these compounds with Cryptococcus IMPDH followed by mass spectrometry analysis showed non-specific and covalent binding with IMPDH at multiple cysteine residues. These results support recent reports that the benzo[b]thiophene 1,1-dioxides moiety as PAINS (pan-assay interference compounds) contributor.
Kummari, Lalith K.,Butler, Mark S.,Furlong, Emily,Blundell, Ross,Nouwens, Amanda,Silva, Alberto B.,Kappler, Ulrike,Fraser, James A.,Kobe, Bostjan,Cooper, Matthew A.,Robertson, Avril A.B.
p. 5408 - 5419
(2018/10/20)

N-(5-Methyl-1,3-Thiazol-2-yl)-2-{[5-((Un)Substituted- Phenyl)1,3,4-Oxadiazol-2-yl]Sulfanyl}acetamides. Unique Biheterocycles as Promising Therapeutic Agents
An electrophile, 2-bromo-N-(5-methyl-1,3-thiazol-2-yl)acetamide, was synthesized by the reaction of 5-methyl-1,3-thiazol-2-amine and bromoacetyl bromide in an aqueous medium. In a parallel scheme, a series of (un)substituted benzoic acids was converted sequentially into respective esters, acid hydrazides, and then into 1,3,4-oxadiazole heterocyclic cores. The electrophile was coupled with the aforementioned 1,3,4-oxadiazoles to obtain the targeted bi-heterocyles. Structural analysis of the synthesized compounds was performed by IR, EI-MS, 1H NMR, and 13C NMR. The enzyme inhibition study of these molecules was carried out against four enzymes, namely, acetylcholinesterase, butyrylcholinesterase, α-glucosidase, and urease. The interactions of these compounds with respective enzymes were recognized by their in silico study. Moreover, their cytotoxicity was also determined to find out their utility as possible therapeutic agents.
Abbasi,Ramzan,Aziz-ur-Rehman,Siddiqui,Shah,Hassan,Seo,Ashraf,Mirza,Ismail
p. 801 - 811
(2019/02/27)

Novel Triazole-Piperazine Hybrid Molecules Induce Apoptosis via Activation of the Mitochondrial Pathway and Exhibit Antitumor Efficacy in Osteosarcoma Xenograft Nude Mice Model
Mitochondria impart a crucial role in the regulation of programmed cell death and reactive oxygen species (ROS) generation, besides serving as a primary energy source. Mitochondria appeared as an important target for the therapy of cancer due to their significant contribution to cell survival and death. Here, we report the design and synthesis of a novel series of triazole-piperazine hybrids as potent anticancer agents. MCS-5 emerged as an excellent anticancer agent which showed better anticancer activity than the standard drug doxorubicin in in vitro and in vivo studies. MCS-5 displayed an IC50 value of 1.92 μM and induced apoptosis in Cal72 (human osteosarcoma cell line) cells by targeting the mitochondrial pathway. This compound arrested the G2/M phase of the cell cycle and induced ROS production and mitochondrial potential collapse in Cal72 cells. MCS-5 displayed excellent anticancer activity in the Cal72 xenograft nude mice model, where it significantly reduced tumor progression, leading to enhanced life span in treated animals compared to control and doxorubicin treated animals without exerting noticeable toxicity. In addition, a 2DG optical probe guided study clearly evoked that MCS-5 remarkably reduced tumor metastasis in the Cal72 xenograft nude mice model. These results indicate that MCS-5 appeared as a novel chemical entity which is endowed with excellent in vitro as well as in vivo anticancer activity and may contribute significantly to the management of cancer in the future.
Mishra, Chandra Bhushan,Mongre, Raj Kumar,Kumari, Shikha,Jeong, Dong Kee,Tiwari, Manisha
p. 753 - 768
(2017/03/24)

Inhibitory growth evaluation and apoptosis induction in MCF-7 cancer cells by new 5-aryl-2-butylthio-1,3,4-oxadiazole derivatives
Background: Cancer has become one of the global health issues and it is the life-threatening disease characterized by unrestrained growth of cells. Despite various advances being adopted by chemotherapeutic management, the use of the current anticancer drugs such as Doxorubicin, Asparginase, Methotrexate, Vincristine remains limited due to high toxicity, side effects and developing drug resistance. Apoptosis is a crucial cellular process and improper regulation of apoptotic signaling pathways may lead to cancer formation. Subsequently, the synthesis of effective chemotherapeutic agents that can induce apoptosis in tumor cell has emerged as a significant approach in cancer drug discovery. Methods: The goal of this work is to develop a potential antitumor agent exerting significant inhibitory effects on cancer cell and low cytotoxicity, for which we focused on the structural features of 1,3,4-oxadiazoles as it a privileged scaffold in modern medicinal chemistry and have the ability to inhibit growth factors, enzymes and kinases potentially involved in the attainment of cellular immortality and carcinogenesis. Result: In vitro MTT screening assay showed the compound 5-aminophenyl-2-butylthio-1,3,4-oxadiazole (5e) showing the highest inhibitory effect against MCF-7 cancer cell with IC50 value 10.05?±?1.08?μM while it is much safer and less toxic on normal cell line (HEK-293). The dose-dependent treatment of MCF-7 cells with 5e resulted in inhibition of cell migration in the wound healing assay. The flow-cytometry analysis showed the cells arrested in G0/G1 phase of the cell cycle. Compound 5e induced apoptosis of MCF-7 cells was characterized using DAPI staining and Annexin V-PE/7-AAD dual binding assay. Reduction of NBT by compound 5e showed a reduced generation of ROS. Western blotting studies showed high activation of apoptotic protein Caspase3 and decrease in expression of anti-apoptotic protein BCL-2. Conclusion: Based on the results of in vitro studies, it could be concluded that compound 5e showed a significant inhibitory growth effect on MCF-7 cells and have the potential to be developed as lead molecule and further structural modifications may result in promising new anticancer agents.
Khanam, Rashmin,Ahmad, Kamal,Hejazi, Iram I.,Siddique, Ibrar A.,Kumar, Vikash,Bhat, Abdul Roouf,Azam, Amir,Athar, Fareeda
p. 1027 - 1042
(2017/10/06)

1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases
Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole–thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC50 values toward plasmodial glyoxalase II were in the 10 μm range.
Sevaille, Laurent,Gavara, Laurent,Bebrone, Carine,De Luca, Filomena,Nauton, Lionel,Achard, Maud,Mercuri, Paola,Tanfoni, Silvia,Borgianni, Luisa,Guyon, Carole,Lonjon, Pauline,Turan-Zitouni, Gülhan,Dzieciolowski, Julia,Becker, Katja,Bénard, Lionel,Condon, Ciaran,Maillard, Ludovic,Martinez, Jean,Frère, Jean-Marie,Dideberg, Otto,Galleni, Moreno,Docquier, Jean-Denis,Hernandez, Jean-Fran?ois
p. 972 - 985
(2017/06/27)

Stable and Rapid Thiol Bioconjugation by Light-Triggered Thiomaleimide Ring Hydrolysis
Maleimide-mediated thiol-specific derivatization of biomolecules is one of the most efficacious bioconjugation approaches currently available. Alarmingly, however, recent work demonstrates that the resulting thiomaleimide conjugates are susceptible to breakdown via thiol exchange reactions. Herein, we report a new class of maleimides, namely o-CH2NHiPr phenyl maleimides, that undergo unprecedentedly rapid ring hydrolysis after thiol conjugation to form stable thiol exchange-resistant conjugates. Furthermore, we overcome the problem of low shelf lives of maleimide reagents owing to their propensity to undergo ring hydrolysis prior to bioconjugation by developing a photocaged version of this scaffold that resists ring hydrolysis. UV irradiation of thiol bioconjugates formed with this photocaged maleimide unleashes rapid thiomaleimide ring hydrolysis to yield the desired stable conjugates within 1 h under gentle, ice-cold conditions.
Kalia, Dimpy,Pawar, Sharad P.,Thopate, Jyoti S.
supporting information
p. 1885 - 1889
(2017/02/05)

Synthesis, biological activities and SAR studies of new 3-substitutedphenyl-4-substitutedbenzylideneamino-1,2,4-triazole Mannich bases and bis-Mannich bases as ketol-acid reductoisomerase inhibitors
A series of new 3-substitutedphenyl-4-substitutedbenzylideneamino-1,2,4-triazole Mannich bases and bis-Mannich bases were synthesized through Mannich reaction with high yields. Their structures were confirmed by means of IR, 1H NMR, 13C NMR and elemental analysis. The preliminary bioassay indicated that compounds 7g, 7h and 7l exhibited potent in vitro inhibitory activities against ketol-acid reductoisomerase (KARI) with Ki value of (0.38 ± 0.25), (6.59 ± 2.75) and (8.46 ± 3.99) μmol/L, respectively, and were comparable with IpOHA. They could be new KARI inhibitors for follow-up research. Some of the title compounds also exhibited obvious herbicidal activities against Echinochloa crusgalli and remarkable in vitro fungicidal activities against Physalospora piricola and Rhizoctonia cerealis. The SAR of the compounds were analyzed, in which the molecular docking revealed the binding mode of 7g with the KARI, and the 3D-QSAR results provided useful information for guiding further optimization of this kind of structures to discover new fungicidal agents towards Rhizoctonia cerealis.
Wang, Bao-Lei,Zhang, Li-Yuan,Liu, Xing-Hai,Ma, Yi,Zhang, Yan,Li, Zheng-Ming,Zhang, Xiao
supporting information
p. 5457 - 5462
(2017/11/17)

Synthesis and Biological Activity of Anthranilic Diamide Derivatives Incorporating 1,3,4-oxadiazole or Nitrogen-containing Saturated Heterocyclic Moieties
A series of novel anthranilic diamide derivatives incorporating 1,3,4-oxadiazole or nitrogen-containing saturated heterocyclic moieties were synthesized, characterized, and evaluated for bacteriostatic activity against three phytopathogenic bacteria Xanthomonas oryzae pv. Oryzae (Xoo), Xanthomonas axonopodis pv. Citri (Xac), Ralstonia solanacearum (R. solanacearum). The preliminary biological results indicated that most compounds exhibit bacteriostatic activity against three phytopathogenic bacteria. Among these compounds, compounds 6g, 6f, and 6i displayed better antibacterial activity. In the test with concentration of 200 μg/mL, antibacterial activity of compound 6i and 6j was 96%. In particular, the bacteriostatic activity displayed by compound 6h against Xoo is similar to the one displayed by commercial drug bismerthiazol.
Zhou, Wen-Juan,Zhang, Li,Xiao, Wei,Chen, He-Ju,Wu, Wen-Neng,Ouyang, Gui-Ping
p. 1423 - 1429
(2017/03/27)

Design, synthesis, biological evaluation, and 3D-QSAR analysis of podophyllotoxin–dioxazole combination as tubulin targeting anticancer agents
The advancement of cancer-fighting drugs has never been a simple linear process. Those drug design professionals begin to find inspiration from the nature after failing to find the ideal products by creative drug design and high-throughput screening. To obtain new molecules for inhibiting tubulin, podophyllotoxin was adopted as the leading compound and 1,3,4-oxadiazole was brought in to the C-4 site of podophyllotoxin in this research. A series of seventeen podophyllotoxin-derived esters have been achieved and then evaluated their antitumor activities against four different cancer cell lines: A549, MCF-7, HepG2, and HeLa. Among all the compounds, compound 7c showed the best antiproliferating properties with IC50?=?2.54?±?0.82?μm against MCF-7 cancer cell line. It was obvious that the content of ROS grew significantly in MCF-7 in a way depending on the dosage. The time- and dose-dependent cell cycle assays revealed that compound 7c could apparently block cell cycle in the phase of G2/M along with the upregulation of cyclin A2 and CDK2 protein. According to further studies, confocal microscopy experiment has certified that compound 7c could restrain cancer from growing by blocking the polymerization of microtubule. Meanwhile, compound 7c could be ideally integrated with the colchicine site of tubulin. In future, it would be feasible to selectively design tubulin inhibitors with the help of 3D-QSAR. This means that it is hopeful to develop compound 7c as a potential agent against cancer due to its biological characteristics.
Wang, Zi-Zhen,Sun, Wen-Xue,Wang, Xue,Zhang, Ya-Han,Qiu, Han-Yue,Qi, Jin-Liang,Pang, Yan-Jun,Lu, Gui-Hua,Wang, Xiao-Ming,Yu, Fu-Gen,Yang, Yong-Hua
p. 236 - 243
(2017/07/13)

Synthesis and antiviral evaluation of novel 1,3,4-oxadiazole/thiadiazole-chalcone conjugates
A series of novel 1,3,4-oxadiazole/thiadiazole–chalcone conjugates were synthesized and their in vitro and in vivo antiviral activities were evaluated via microscale thermophoresis method and half-leaf method, respectively. The in vitro results indicated that compounds 7g, 7l, 8h, and 8l displayed good antiviral activity against TMV, with the binding constant values of 5.93, 6.15, 6.02, and 5.04 μM, respectively, which were comparable to that of Ninnanmycin (6.78 μM) and even better than that of Ribavirin (99.25 μM). The in vivo results demonstrated that compounds 7g, 7l, 8h, and 8l exhibited remarkable anti-TMV activity with the EC50 values of 33.66, 33.97, 33.87 and 30.57 μg/mL, respectively, which were comparable to that of Ningnanmycin (36.85 μg/mL) and superior to that of Ribavirin (88.52 μg/mL). Interestingly, the trend of antiviral activity in vivo was consistent with the in vitro results.
Gan, Xiuhai,Hu, Deyu,Chen, Zhuo,Wang, Yanjiao,Song, Baoan
p. 4298 - 4301
(2017/09/12)

Synthesis, spectral analysis and antibacterial evaluation of 5-substituted-1,3,4-oxadiazol-2-yl 4-(4-methylpiperidin-1-ylsulfonyl)benzyl sulfides
Owing to valuable biological activities of 1,3,4-oxadiazole, sulfamoyl and piperidine functionalities, some new 1-(4-{[(5-substituted-1,3,4-oxadiazol-2-yl) thio]methyl}benzene sulfonyl)-4-methylpiperidine (6a-o) derivatives have been introduced. The target molecules were synthesized from different aralkyl/aryl carboxylic acids, 1a-o, through a series of steps. First the compounds, 1a-o, were converted to heterocyclic 1,3,4-oxadiazole nucleophiles, 4a-o. Second an electrophile as 1-(4-bromomethylbenzenesulfonyl)-4-methylpiperidine (5) was synthesized from 4-methylpiperidine. Finally the target compounds, 6a-o, were prepared by reacting 4a-o with 5 in DMF and LiH. The final compounds were structurally elucidated by spectral data of IR, 1H-NMR and EI-MS. All the compounds were screened for their antibacterial evaluation and found to exhibit valuable results.
Aziz-Ur-Rehman,Ahtzaz, Samreen,Abbasi, Muhammad Athar,Siddiqui, Sabahat Zahra,Rasool, Shahid,Ahmad, Irshad
p. 3370 - 3375
(2017/05/22)

Synthesis and pharmacological screening: Sulfa derivatives of 2-pipecoline-bearing 1,3,4-oxadiazole core
An electrophile, 1-(4-(bromomethylbenzenesulfonyl)-2-methylpiperidine, was synthesized by the reaction of 2-methylpiperidine (2-pipecoline) and 4-bromomethylbenzenesulfonyl chloride in a weak basic medium under pH control. A series of nucleophiles, 5-aryl/aralkyl-1,3,4-oxadiazol-2-thiols, were synthesized from corresponding carboxylic acids in three steps. The title molecules were synthesized by coupling the electrophile to nucleophiles in an aprotic medium using LiH as an activator. The structures of all synthesized compounds were corroborated through IR, 1H NMR, and EI-MS techniques. All the compounds were screened for their pharmacological behavior, particularly, antibacterial and enzyme inhibitory activities. Notably efficient results were obtained against both gram-positive and gram-negative bacterial strains. Regarding enzyme inhibition, compounds were efficient against acetylcholinesterase and butyrylcholinesterase.
Aziz-ur-Rehman,Arif,Abbasi,Siddiqui,Rasool,Shah
p. 328 - 339
(2017/07/04)

Synthesis and biological evaluation of 1, 2, 4-triazoles and 1, 3, 4-oxadiazoles derivatives linked to 1, 4-dihydropyridines scaffold
A series of diethyl-2, 6-dimethyl-4-phenyl-1, 4-dihydropyridine-3, 5-dicarboxylate derivative coupled to 1, 3, 4-oxadiazole-5-thiones and 1, 2, 4-triazole-5-thiones moieties at C2, C6 positions of 1, 4-dihydropyridine ring system was prepared. This linkage was carried out by the reaction of 1, 3, 4-oxadiazole-5-thiones and 1, 2, 4-triazole-5-thiones with 2, 6-dibromomethyl-3, 5-diethoxycarbonyl-4-phenyl-1, 4-dihydropyridine in the presence of potassium carbonate as a weak base and dry acetone as the solvent. The newly synthesized compounds were characterized by FT-IR, 1H NMR, 13C NMR spectral data, elemental analysis and FAB-MS. The synthesized compounds were tested for their antimicrobial and antifungal activity against Escherichia coli and Aspergillus fumigatus in vitro in comparison with Enrofloxacin and Amphotericin as the reference drugs which are normally used for treating such infections. The synthetic compounds showed different inhibition zones against tested bacteria and fungi. Compound 8d showed more antagonistic activity against E. coli and A. fumigatus.
Ziaie, Maghsoud,Dilmaghani, Karim Akbari,Tukmechi, Amir
p. 895 - 901
(2018/01/17)

Synthesis and biological activities of cyclanone O-(2-(3-aryl-4- amino-4H-1,2,4-triazol-3-yl)thio)acetyl)oxime derivatives
Twelve cyclanone O-(2-(3-aryl-4-amino-4H-1,2,4-triazol-3-yl)thio)acetyl)oxime derivatives were synthesized and their structures were confirmed by spectroscopy (IR, 1H NMR, 13C NMR, 19F NMR) and elemental analysis. Their antifungal and antibacterial activities were evaluated against six fungi (Gibberella zeae, Fusarium oxysporum, Clematis mandshurica, Phytophthora infestans, Paralepetopsis sasakii, Sclerotinia sclerotiorum) and two bacteria (Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas citri subsp. Citri (Xcc)). The results indicated that most of the title compounds exhibited good antibacterial activities. Among them, compounds 6d, 6g, 6h, and 6j showed better antibacterial activities against Xoo and Xcc than that of the commercial agent thiodiazole-copper.
Chen, Meihang,Chen, Lijuan,Zhu, Xuesong,Wang, Xiaobin,Li, Qin,Zhang, Juping,Lu, Daowang,Xue, Wei
p. 1259 - 1263
(2017/10/18)

Elemental sulfur as a sulfuration agent in the copper-catalyzed C-H bond thiolation of electron-deficient arenes
By utilizing elemental sulfur as the thiolation agent and oxidant, a copper-catalyzed direct C-H bond thiolation of electron-deficient arenes was demonstrated. Various electron-deficient arenes were proved to be suitable for this transformation. Preliminary mechanistic studies indicated that this reaction underwent a radical pathway, in which the trisulfur radical anion (S3-) might play a vital role. Meanwhile, KIE experiments suggested that C-H bond cleavage was not involved in the rate-determining step.
Yan, Haiming,Huang, Zhiliang,Chen, Meng,Li, Cuiting,Chen, Ya,Gao, Meng,Lei, Aiwen
supporting information
p. 8276 - 8279
(2017/10/23)

Novel 1,3,4-oxadiazole/oxime hybrids: Synthesis, docking studies and investigation of anti-inflammatory, ulcerogenic liability and analgesic activities
A novel group of 1,3,4-oxadaiazoles, a group known for their anti-inflammatory activity, is hybridized with nitric oxide (NO) releasing group, oxime, for its gastro-protective action and potential synergistic effect. The synthesized hybrids were evaluated for their anti-inflammatory, analgesic, antioxidant and ulcerogenic activities. Most of the tested compounds showed excellent anti-inflammatory activity with compound 8e being more active than indomethacin. They also showed moderate analgesic activity but no antioxidant one. The ability of the synthesized compounds to inhibit COX-1 and COX-2 is studied and the prepared compounds were able to inhibit both COXs non-selectively with IC50s of 0.75–70.50?μM. Docking studies revealed the mode of interaction of the tested compounds into the empty pocket of the isozymes. All of the synthesized compounds interact with COXs active site with energy scores comparable to that of ibuprofen. All compounds showed a safer profile on the stomach tissue integrity compared to conventional NSAIDs. The designed strategy was applied to ibuprofen to introduce ibuprofen/oxadiazole/NO hybrid. The synthesized ibuprofen hybrid is a promising alternative to ibuprofen having similar anti-inflammatory activity but with safer GIT profile.
Abd-Ellah, Heba S.,Abdel-Aziz, Mohamed,Shoman, Mai E.,Beshr, Eman A.M.,Kaoud, Tamer S.,Ahmed, Al-Shaimaa F.F.
supporting information
p. 48 - 63
(2016/09/28)

Synthesis of a series of novel tetra-tert-butylcalix[4]arene linked to 1,2,4-triazole and 1,3,4-oxadiazole derivatives
A series of tetra-tert-butylcalix[4]arene linked to 1,2,4-triazole-5-thiones and 1,3,4-oxadiazole-5-thiones derivatives at lower rim were synthesized by the reaction of 1,2,4-triazole-5-thione and 1,3,4-oxadiazole-5-thione with 5,11,17,23-tetra-tert-butyl-25,27-bis(3-bromopropoxy)-26,28-dihydroxycalix[4]arene (2). The synthesized compounds were characterized by FT-IR, 1H NMR, 13C NMR spectral data, elemental analysis and ESI-MS.
Ghezelbash, Zahra Dono,Dilmaghani, Karim Akbari
p. 790 - 797
(2016/12/18)

1,2,4-triazole compound containing oxime carboxylate, and preparation method and application thereof
The invention discloses a 1,2,4-triazole compound containing oxime carboxylate, and a preparation method and application thereof. The general formula (I) of the compound is described in the specification. In the formula (I), R is selected from a group consisting of a phenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-trifluoromethylphenyl group, a 4-nitrophenyl group, a 4-methoxyphenyl group, a 3,4-dimethyoxyphenyl group and a 3,4,5-trimethoxyphenyl group; R1 is a methyl group or ethyl group; and R2 is a methyl group. The compound provided by the invention has good biological activity in inhibition of Xanthomonas axonopodis pv.citri, Ralstonia solanacearum and Xanthomonas oryzae pv.oryzae.
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Paragraph 0020; 0024

(2018/02/04)

Containing 1, 3, 4-oxadiazole of 4-hydroxy-pyrroline-2-one derivatives, its preparation method and application (by machine translation)
This invention relates to a containing 1, 3, 4-oxa-dizole of the 4 [...] hydroxy pyrroline -2 the derivatives [...], preparation method and application thereof, the structure represented by general formula (I) are as follows: In the type I:R 1 to substituted aromatic hydrocarbon, substituted benzyl; R 2 to substituted aromatic hydrocarbon, hydrogen. The invention has better anti-bacteria and anti-plant-virus activity, and the compound is stable. (by machine translation)
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Paragraph 0018

(2016/10/31)

Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis
Herein, we report the discovery and structure-activity relationships of 5-substituted-2-[(3,5-dinitrobenzyl)sulfanyl]-1,3,4-oxadiazoles and 1,3,4-thiadiazoles as a new class of antituberculosis agents. The majority of these compounds exhibited outstanding in vitro activity against Mycobacterium tuberculosis CNCTC My 331/88 and six multidrug-resistant clinically isolated strains of M. tuberculosis, with minimum inhibitory concentration values as low as 0.03 μM (0.011-0.026 μg/mL). The investigated compounds had a highly selective antimycobacterial effect because they showed no activity against the other bacteria or fungi tested in this study. Furthermore, the investigated compounds exhibited low in vitro toxicities in four proliferating mammalian cell lines and in isolated primary human hepatocytes. Several in vitro genotoxicity assays indicated that the selected compounds have no mutagenic activity. The oxadiazole and thiadiazole derivatives with the most favorable activity/toxicity profiles also showed potency comparable to that of rifampicin against the nonreplicating streptomycin-starved M. tuberculosis 18b-Lux strain, and therefore, these derivatives, are of particular interest.
Karabanovich, Galina,Zemanová, Júlia,Smutny, Tomá?,Székely, Rita,?arkan, Michal,Centárová, Ivana,Vocat, Anthony,Pávková, Ivona,?onka, Patrik,Něme?ek, Jan,Stola?íková, Ji?ina,Vejsová, Marcela,Vávrová, Kate?ina,Klime?ová, Věra,Hrabálek, Alexandr,Pávek, Petr,Cole, Stewart T.,Miku?ová, Katarína,Roh, Jaroslav
supporting information
p. 2362 - 2380
(2016/04/09)

1,2,4-Triazolethione derivative containing (hetero)aryl group and piperazine, and preparation method and application thereof
The invention discloses a 1,2,4-triazolethione derivative containing a (hetero)aryl group and piperazine, and a preparation method and an application thereof. The synthesis method has the advantages of few reaction steps, simple and mild conditions, simple operation and high yield. The derivative has a structural formula represented by general formula I and general formula II, and R, R and R in the general formula I and the general formula II are as defined in claim 1. The above compounds have certain in vitro inhibition activity to cucumber fusarium wilt, Cercospora arachidicola Hori, Macrophoma kawatsukai, Altemaria solani, Fusarium graminearum, Rhizoctonia cerealis and other plant pathogens, and especially have high in vitro inhibition activity on the cucumber fusarium wilt, Cercospora arachidicola Hori, Macrophoma kawatsukai and Rhizoctonia cerealis. The compounds of the general formula I and general formula II simultaneously have rice KARI enzyme in vitro inhibition activity. The derivative is suitable for comprehensive control of fungus damages on various crops.
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Paragraph 0057; 0058; 0059; 0060; 0061

(2016/10/07)

Piperazine-contained 1,3,4-oxadiazole Mannich base compound, and preparation and application thereof
The invention discloses a piperazine-contained 1,3,4-oxadiazole Mannich base compound, and preparation and application thereof. The compound provided by the invention has the structural formulae shown in general formulae I and II, wherein in the formulae, R1 and R2 are defined according to Claim 1. The compound having the general formulae I and II has high-efficiency KARI enzyme restraining activity, higher weed control activity and particularly significance for activity of dicotyledon oilseed rape; meanwhile, the compound has a certain bactericidal activity, an in-vitro restraining activity for fusarium wilt of cucumber, mycosphaerella arachidicola, rhizoctonia cerealis, ceratobasidium cornigerum, alternaria solani, fusarium asiaticum and the like, and particularly significant effect on rhizoctonia cerealis. The piperazine-contained 1,3,4-oxadiazole Mannich base compound disclosed by the invention is applicable for efficient inhibition for KARI enzyme activity, and comprehensive control for weed and fungus damage on various crops.
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Paragraph 0022

(2016/10/09)