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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)

Discovery of an Orally Efficacious MYC Inhibitor for Liver Cancer Using a GNMT-Based High-Throughput Screening System and Structure-Activity Relationship Analysis
Glycine-N-methyl transferase (GNMT) downregulation results in spontaneous hepatocellular carcinoma (HCC). Overexpression of GNMT inhibits the proliferation of liver cancer cell lines and prevents carcinogen-induced HCC, suggesting that GNMT induction is a potential approach for anti-HCC therapy. Herein, we used Huh7 GNMT promoter-driven screening to identify a GNMT inducer. Compound K78 was identified and validated for its induction of GNMT and inhibition of Huh7 cell growth. Subsequently, we employed structure-activity relationship analysis and found a potent GNMT inducer, K117. K117 inhibited Huh7 cell growth in vitro and xenograft in vivo. Oral administration of a dosage of K117 at 10 mpk (milligrams per kilogram) can inhibit Huh7 xenograft in a manner equivalent to the effect of sorafenib at a dosage of 25 mpk. A mechanistic study revealed that K117 is an MYC inhibitor. Ectopic expression of MYC using CMV promoter blocked K117-mediated MYC inhibition and GNMT induction. Overall, K117 is a potential lead compound for HCC- and MYC-dependent cancers.
Kant, Rajni,Yang, Ming-Hui,Tseng, Chih-Hua,Yen, Chia-Hung,Li, Wei-You,Tyan, Yu-Chang,Chen, Marcelo,Tzeng, Cherng-Chyi,Chen, Wei-Cheng,You, Kaiting,Wang, Wen-Chieh,Chen, Yeh-Long,Chen, Yi-Ming Arthur
p. 8992 - 9009
(2021/07/19)

Synthesis and biological evaluation of honokiol derivatives bearing 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)oxazol-2(3h)-ones as potential viral entry inhibitors against sars-cov-2
The 2019 coronavirus disease (COVID-19) caused by SARS-CoV-2 virus infection has posed a serious danger to global health and the economy. However, SARS-CoV-2 medications that are specific and effective are still being developed. Honokiol is a bioactive component from Magnoliae officinalis Cortex with damp-drying effect. To develop new potent antiviral molecules, a series of novel honokiol analogues were synthesized by introducing various 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)oxazol-2(3H)-ones to its molecule. In a SARS-CoV-2 pseudovirus model, all honokiol derivatives were examined for their antiviral entry activities. As a result, 6a and 6p demonstrated antiviral entry effect with IC50 values of 29.23 and 9.82 μM, respectively. However, the parental honokiol had a very weak antiviral activity with an IC50 value more than 50 μM. A biolayer interfero-metry (BLI) binding assay and molecular docking study revealed that 6p binds to human ACE2 protein with higher binding affinity and lower binding energy than the parental honokiol. A competitive ELISA assay confirmed the inhibitory effect of 6p on SARS-CoV-2 spike RBD’s binding with ACE2. Importantly, 6a and 6p (TC50 > 100 μM) also had higher biological safety for host cells than honokiol (TC50 of 48.23 μM). This research may contribute to the discovery of potential viral entrance inhibitors for the SARS-CoV-2 virus, although 6p’s antiviral efficacy needs to be validated on SARS-CoV-2 viral strains in a biosafety level 3 facility.
Bai, Li-Ping,Guo, Yong,Jiang, Zhi-Hong,Liu, Jia-Zheng,Meng, Jie-Ru,Xu, Ting,Zheng, Zhi-Yuan
(2021/09/08)

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)

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 phenyltriazole thiol-based derivatives as highly potent inhibitors of DCN1-UBC12 interaction
Defective in cullin neddylation 1(DCN1) is a co-E3 ligase that is important for cullin neddylation. Dysregulation of DCN1 highly correlates with the development of various cancers. Herein, from the initial high-throughput screening, a novel hit compound 5a containing a phenyltriazole thiol core (IC50 value of 0.95 μM for DCN1-UBC12 interaction) was discovered. Further structure-based optimization leads to the development of SK-464 (IC50 value of 26 nM). We found that SK-464 not only directly bound to DCN1 in vitro, but also engaged cellular DCN1, suppressed the neddylation of cullin3, and hindered the migration and invasion of two DCN1-overexpressed squamous carcinoma cell lines (KYSE70 and H2170). These findings indicate that SK-464 may be a novel lead compound targeting DCN1-UBC12 interaction.
Zhou, Wenjuan,Xu, Chenhao,Dong, Guanjun,Qiao, Hui,Yang, Jing,Liu, Hongmin,Ding, Lina,Sun, Kai,Zhao, Wen
(2021/03/24)

N-Amino-1,8-Naphthalimide is a Regenerated Protecting Group for Selective Synthesis of Mono-N-Substituted Hydrazines and Hydrazides
A new route to synthesis of various mono-N-substituted hydrazines and hydrazides by involving in a new C?N bond formation by using N-amino-1,8-naphthalimide as a regenerated precursor was invented. Aniline and phenylhydrazines are reproduced upon reacting these individually with 1,8-naphthalic anhydride followed by hydrazinolysis. The practicality and simplicity of this C?N dihalo alkanes; developed a synthon for bond formation protocol was exemplified to various hydrazines and hydrazides. N-amino-1,8-naphthalimide is suitable synthon for transformation for selective formation of mono-substituted hydrazine and hydrazide derivatives. Those are selective mono-amidation of hydrazine with acid halides; mono-N-substituted hydrazones from aldehydes; synthesis of N-aminoazacycloalkanes from acetohydrazide scaffold and inserted to hydroxy derivatives; distinct synthesis of N,N-dibenzylhydrazines and N-benzylhydrazines from benzyl halides; synthesis of N-amino-amino acids from α-halo esters. Ecofriendly reagent N-amino-1,8-naphthalimide was regenerated with good yields by the hydrazinolysis in all procedures.
Manoj Kumar, Mesram,Venkataramana, Parikibanda,Yadagiri Swamy, Parikibanda,Chityala, Yadaiah
supporting information
p. 17713 - 17721
(2021/11/10)

Iron-catalyzed oxidative amidation of acylhydrazines with amines
A new approach for amide bond formation via a mild and efficient Iron-catalyzed cross-coupling reaction of acylhydrazines and amines using TBHP as oxidant is described. This protocol is compatible with a wide range of amines and acylhydrazines. In addition, the synthetic application of the reaction is presented.
Wang, Yi-Jie,Zhang, Guo-Yu,Shoberu, Adedamola,Zou, Jian-Ping
supporting information

(2021/08/18)

Oxazole ring-containing honokiol thioether derivative and preparation method and application thereof
The invention discloses an oxazole ring-containing honokiol thioether derivative, a preparation method thereof and application of the oxazole ring-containing honokiol thioether derivative as an alpha-glucosidase inhibitor, the chemical structure of the oxazole ring-containing honokiol thioether derivative is shown as a general formula (I), and R is selected from non-substituted or substituted phenyl. Compared with the prior art, the invention provides the novel honokiol thioether derivative containing the oxazole ring, and the honokiol thioether derivative containing the oxazole ring has good inhibitory activity on alpha-glucosidase, provides more possibilities for treating diabetes, and is expected to be used for preparing novel candidate drug molecules for treating diabetes. In addition, the preparation process is simple, the cost is low, and the yield is high.
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Paragraph 0042; 0045-0046

(2021/08/11)

Design, synthesis, biological activity, crystal structure and theoretical calculations of novel 1,2,4-triazole derivatives
Series of 1,2,4-triazole Schiff base (Ia-f) were designed and synthesized. Their in-vitro antifungal activity to pythium solani, gibberlla nicotiancola, fusarium oxysporium fs.p. niveum and gibberlla saubinetii were evaluated. The results showed compound If exhibited good activity with tested fungi, which indicated that 1,2,4-triazole scaffold with introduction of imidazole phenyl could keep the antifungal activity. In order to further research the compound If, the crystal structure was detected by X-ray diffraction. Meanwhile, the FT-IR, FT-Raman, natural bond orbital (NBO), HOMO-LUMO and MEP were calculated at B3LYP/6-311G+(d,p) level. All the results will be helpful for further drug design in 1,2,4-triazole analogues.
Jin, Ruyi,Wang, Yanyan,Guo, Hui,Long, Xu,Li, Jiajia,Yue, Shijun,Zhang, Shuan,Zhang, Guanghui,Meng, Qinghua,Wang, Chuan,Yan, Hao,Tang, Yuping,Zhou, Sha
(2019/10/28)

5-substituent-1, 2, 4-triazole-thioketone Schiff base compound as well as preparation method and application thereof
The invention belongs to the technical field of chemical medicines, and relates to a 5-substituent 1, 2, 4-triazole thioketone Schiff base compound as well as a preparation method and application thereof. An intermediate (I) or an intermediate (II) is subjected to reflux reaction with 3, 5-dimethyl 4-hydroxy benzaldehyde in glacial acetic acid respectively, filtering and drying are performed to obtain the 5-substituent -1, 2, 4-triazole thioketone Schiff base compound. According to the 5-substituent-1, 2, 4-triazole-thioketone Schiff base compound as well as the preparation method and application thereof of the invention, an active group-- imino is introduced into a triazole ring matrix to prepare and synthesize a series of triazole Schiff base compounds with multiple active sites, and thetriazole Schiff base compounds have the advantages of good activity, small dosage, small toxic and side effects, safety and environmental protection; meanwhile, the compounds can be used as crop antifungal agents and can influence the synthesis of fungal cell walls, so that the growth and proliferation of fungi are inhibited, and finally, an antibacterial or bactericidal effect is achieved.
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Paragraph 0100; 0104

(2021/01/04)

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs
The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone (6), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (fu brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone (42), a DORA with improved in vivo efficacy compared to 6.
Bolli, Martin H.,Boss, Christoph,Brotschi, Christine,Gatfield, John,Heidmann, Bibia,Jenck, Francois,Roch, Catherine,Sifferlen, Thierry,Treiber, Alexander,Williams, Jodi T.
supporting information

(2020/01/25)

Pharmacomodulations of the benzoyl-thiosemicarbazide scaffold reveal antimicrobial agents targeting D-alanyl-D-alanine ligase in bacterio
D-Alanyl-D-alanine ligase (Ddl) is a validated and attractive target among the bacterial enzymes involved in peptidoglycan biosynthesis. In the present work, we investigated the pharmacomodulations of the benzoylthiosemicarbazide scaffold to identify new Ddl inhibitors with antibacterial potency. Five novel series of thiosemicarbazide analogues, 1,2,4-thiotriazole-3-thiones, 1,3,4-thiadiazoles, phenylthiosemicarbazones, diacylthiosemicarbazides and thioureas were synthesized via straightforward procedures, then tested against Ddl and on susceptible or resistant bacterial strains. Among these, the thiosemicarbazone and thiotriazole were identified as the most promising scaffolds with Ddl inhibition potency in the micromolar range. Antimicrobial evaluation of salicylaldehyde-4(N)-(3,4-dichlorophenyl) thiosemicarbazone 33, one of the best compounds in our study, revealed interesting antimicrobial activities with values of 3.12–6.25 μM (1.06–2.12 μg/mL) against VRE strains and 12.5–25.0 μM (4.25–8.50 μg/mL) towards MRSA and VRSA strains. A detailed mechanistic study was conducted on the Ddl inhibitors 4-(3,4-dichlorophenyl)-5-(2-hydroxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 20 and compound 33, and revealed a bactericidal effect at 5 × MIC concentration after 7 h and 24 h, respectively, and a bacteriostatic effect at 1 × MIC or 2 × MIC without any sign of bacterial membrane disruption at these lower concentrations. Finally, 20 and 33 were proved to target Ddl in bacterio via intracellular LC-MS dosage of D-Ala, L-Ala and D-Ala-D-Ala. Although, at this stage, our results indicate that other mechanisms might be involved to explain the antimicrobial potency of our compounds, their ability to inhibit the growth of strains resistant to usual antibiotics, as well as strains that express alternative ligases, sets the stage for the development of new antimicrobial agents potentially less sensitive to resistance mechanisms.
Ameryckx, Alice,Pochet, Lionel,Wang, Gang,Yildiz, Esra,Saadi, Bouazza Es,Wouters, Johan,Van Bambeke, Fran?oise,Frédérick, Rapha?l
supporting information

(2020/06/03)

Discovery of [1,2,4]triazole derivatives as new metallo-β-lactamase inhibitors
The emergence and spread of metallo-β-lactamase (MBL)-mediated resistance to β-lactam antibacterials has already threatened the global public health. A clinically useful MBL inhibitor that can reverse β-lactam resistance has not been established yet. We here report a series of [1,2,4]triazole derivatives and analogs, which displayed inhibition to the clinically relevant subclass B1 (Verona integron-encoded MBL-2) VIM-2. 3-(4-Bromophenyl)-6,7-dihydro-5H-[1,2,4]triazolo [3,4-b][1,3]thiazine (5l) manifested the most potent inhibition with an IC50 (half-maximal inhibitory concentration) value of 38.36 μM. Investigations of 5l against other B1 MBLs and the serine β-lactamases (SBLs) revealed the selectivity to VIM-2. Molecular docking analyses suggested that 5l bound to the VIM-2 active site via the triazole involving zinc coordination and made hydrophobic interactions with the residues Phe61 and Tyr67 on the flexible L1 loop. This work provided new triazole-based MBL inhibitors and may aid efforts to develop new types of inhibitors combating MBL-mediated resistance.
Yuan, Chen,Yan, Jie,Song, Chen,Yang, Fan,Li, Chao,Wang, Cheng,Su, Huiling,Chen, Wei,Wang, Lijiao,Wang, Zhouyu,Qian, Shan,Yang, Lingling
(2020/01/11)

Synthesis, biological evaluation of benzothiazole derivatives bearing a 1,3,4-oxadiazole moiety as potential anti-oxidant and anti-inflammatory agents
Twenty benzothiazole derivatives bearing a 1,3,4-oxadiazole moiety were synthesized and evaluated for their anti-oxidant and anti-inflammatory activities. Among these compounds, 8h and 8l were appeared to have high radical scavenging efficacies as 0.05 ± 0.02 and 0.07 ± 0.03 mmol/L of IC50 values in ABTS+[rad] bioassay, respectively. In anti-inflammatory tests, compound 8h displayed good activity with 57.35% inhibition after intraperitoneal administration, which was more potent than the reference drug (indomethacin). Molecular modeling studies were performed to investigate the binding mode of the representative compound 8h into COX-2 enzyme. In vitro enzyme study implied that compound 8h exerted its anti-inflammatory activity through COX-2 inhibition.
Bai, Xue-Qian,Cui, Ming-Yue,Li, Chun-Shi,Liang, Cheng-Wu,Song, Ze-Wen,Wang, Hui-Yan,Zhang, Tian-Yi,Zheng, Xian-Jing
(2020/05/08)

Metal beta-lactamase inhibitor
The invention discloses application of a triazole compound, or a stereoisomer thereof, or a salt thereof, or a solvate thereof, represented by formula I in preparation of a metal beta-lactamase inhibitor drug, and belongs to the field of medicinal chemistry. The invention further discloses a preparation method of compounds, and a pharmaceutical composition comprising the compounds.
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Paragraph 0082-0086

(2020/03/11)

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 and synthesis of new norfloxacin-1,3,4-oxadiazole hybrids as antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA)
Toward the search of new antibacterial agents to control methicillin-resistant Staphylococcus aureus (MRSA), a class of new norfloxacin-1,3,4-oxadiazole hybrids were designed and synthesized. Antibacterial activities against drug-sensitive bacteria S. aureus and clinical drug resistant isolates of MRSA were evaluated. Compound 5k exhibited excellent antibacterial activities against S. aureus (MIC: 2 μg/mL) and MRSA1–3 (MIC: 0.25–1 μg/mL). The time-kill kinetics demonstrated that compound 5k had an advantage over commonly used antibiotics vancomycin in killing S. aureus and MRSA. Moreover, compound 5k could inhibit the bacteria and destroy their membranes in a short time, and showed very low cytotoxicity to NRK-52E cells. Some interesting structure-activity relationships (SARs) were also discussed. These results indicated that these norfloxacin-1,3,4-oxadiazole hybrids could be further developed into new antibacterial agents against MRSA.
Guo, Yong,Xu, Ting,Bao, Chongnan,Liu, Zhiyan,Fan, Jiangping,Yang, Ruige,Qin, Shangshang
(2019/07/02)

Investigation on 4-amino-5-substituent-1,2,4-triazole-3-thione Schiff bases an antifungal drug by characterization (spectroscopic, XRD), biological activities, molecular docking studies and electrostatic potential (ESP)
Four novel Schiff bases 4-(2,4-dinitrobenzylideneamino)-5-m-tolyl-2H-1,2,4-triazole-3(4H)-thione) (F1), 4-(2,4-dinitrobenzylideneamino)-5-(2-methoxyphenyl)-2H-1,2,4-triazole-3(4H)-thione) (F2), 4-(2,4-dinitrobenzylideneamino)-5-(3-methoxyphenyl)-2H-1,2,4-triazole-3(4H)-thione) (F3) and 4-(2,4-dinitrobenzylideneamino)-5-(4-methoxyphenyl)-2H-1,2,4-triazole-3(4H)-thione) (F4) were prepared as new antifungal compounds contributing 4-Amino-5-Substituent-1,2,4-Triazole-3-Thione and 2,4-dinitrobenzaldehyde via a condensation reaction under the mild conditions with excellent yields. The structures of compounds were characterized by elemental analysis (EA), FT-IR, 1H NMR, 13C NMR spectra and X-ray analysis. In addition, the compounds were screened for in vitro biological activity, and the bioassay results indicated that the newly synthesized compounds showed different in vitro antifungal activities against five plant fungi. Particularly, compound F3 (EC50 = 11.16 mg/L) was found to be the most active respectively against Wheat gibberellic, even more effective than Fluconazole (EC50 = 16.03 mg/L). The active compounds were further evaluated for enzyme inhibition efficacy against the receptor CYP51 by docking. Meanwhile, an explicit surface analysis on compounds were carried out theoretically using the wave function analyzer (Multiwfn 3.4.1 software) in order to study the reactivity of the compounds.
Wu, Shaojie,Zhang, Wenhui,Qi, Le,Ren, Yinghui,Ma, Haixia
p. 171 - 182
(2019/07/19)

A novel one-pot synthesis method of 3,4,5-triaryl-substituted 1,2,4-triazoles
[Figure not available: see fulltext.] A novel method for the preparation of 3,4,5-triaryl-substituted 1,2,4-triazoles by the reaction of hydrazides with secondary amides in polyphosphoric ester has been developed. The new method is characterized by mild conditions and ease of synthesis, including the stages of isolation and purification of the product. Additionally, product structures were confirmed by counter synthesis. It was shown that the proposed method is suitable for producing 1,2,4-triazoles with phenolic substituents without the stages of the protection and deprotection of the hydroxyl group. Using the new method, five 3,4,5-substituted 1,2,4-triazoles were obtained for the first time.
Yakuschenko, Igor K.,Pozdeeva, Natal’ya N.,Gadomsky, Svyatoslav Ya.
p. 834 - 838
(2019/11/14)

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 biological activities of benzothiazole derivatives bearing a 1,3,4-thiadiazole moiety
A series of benzothiazole derivatives bearing a 1,3,4-thiadiazole moiety were designed, synthesized and evaluated for their antibacterial, antifungal and antiviral activities. The bioassay results indicated that most of target compounds showed good antiviral activities against tobacco mosaic virus (TMV) and antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) and Ralstonia solanacearum (Rs). Especially, the anti-Xoo effect of title compounds 5k (N-(5-methoxybenzo[d]thiazol-2-yl)-2-((5-(2-tolyl)-1,3,4-thiadiazol-2-yl)thio)acetamide) and the anti-Rs effect of title compounds 5a (N-(5-nitrobenzo[d]thiazol-2-yl)-2-((5-(4-(trifluorom ethyl)phenyl)-1,3,4-thiadiazol-2-yl)thio)acetmide) respectively reached 52.4% and 71.6% at 100 μg/mL, which are superior to that of bismerthiazol (32.0% and 52.3%). In addition, the protective and inactivation activities of title compound 5i (N-(5-methoxybenzo [d]thiazol-2-yl)-2-((5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)thio)acetamide) against TMV were 79.5% and 88.3%, respectively, which are better than that of ningnanmycin (76.4% and 86.8%). The above research showed that benzothiazole derivatives bearing a 1,3,4-thiadiazole moiety may be used as potential molecular templates in searching for highly-efficient antiviral and antibacterial agents.
Tang, Xu,Wang, Zhongbo,Zhong, Xinmin,Wang, Xiaobin,Chen, Lijuan,He, Ming,Xue, Wei
p. 241 - 248
(2019/01/04)

Design, synthesis, biological activities and DFT calculation of novel 1,2,4-triazole Schiff base derivatives
Series of 1,2,4-triazole Schiff bases (2a-2d, 2f-2h and 3a-3h) have been designed and synthesized. The structure of title compounds was confirmed on the basis of their spectral data and elemental analysis. All the target compounds were screened for their in vitro antifungal activity and antibacterial activity. Two of the tested compounds (2a and 2b) exhibited significant antifungal activity against most fungi, especially compound 2a showed better antifungal activity than triadimefon. Meanwhile, the antibacterial activity assay also indicated compound 2a exhibited excellent antibacterial activities comparable to chloramphenicol. The SAR manifested no substitution at position 5 of the triazole ring caused an increase in activity, and 3-phenoxy phenyl group introduced in 1,2,4-triazole scaffold can enhance the antibacterial activity. The DFT calculation indicated triazole ring, S atom and benzene ring in both of the 2a and 3a make a major contribution to the activity.
Jin, Ru-Yi,Zeng, Chu-Yue,Liang, Xu-Hua,Sun, Xiao-Hong,Liu, Yuan-Fa,Wang, Yan-Yan,Zhou, Sha
p. 253 - 260
(2018/07/06)

Design, synthesis, insecticidal activity and 3D-QSR study for novel trifluoromethyl pyridine derivatives containing an 1,3,4-oxadiazole moiety
A series of trifluoromethyl pyridine derivatives containing 1,3,4-oxadiazole moiety was designed, synthesized and bio-assayed for their insecticidal activity. The result of bio-assays indicated the synthesized compounds exhibited good insecticidal activity against Mythimna separata and Plutella xylostella, most of the title compounds show 100% insecticidal activity at 500 mg L-1 and >80% activity at 250 mg L-1 against the two pests. Compounds E18 and E27 showed LC50 values of 38.5 and 30.8 mg L-1 against Mythimna separata, respectively, which were close to that of avermectin (29.6 mg L-1); compounds E5, E6, E9, E10, E15, E25, E26, and E27 showed 100% activity at 250 mg L-1, which were better than chlorpyrifos (87%). CoMFA and CoMSIA models with good predictability were proposed, which revealed the electron-withdrawing groups with an appropriate bulk at 2- and 4-positions of benzene ring could enhance insecticidal activity.
Xu,Wang,Luo,Yu,Guo,Fu,Zhao,Wu
p. 6306 - 6314
(2018/02/19)

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)

1-(2-Hydroxybenzoyl)-thiosemicarbazides are promising antimicrobial agents targeting D-alanine-D-alanine ligase in bacterio
The bacterial cell wall and the enzymes involved in peptidoglycan synthesis are privileged targets for the development of novel antibacterial agents. In this work, a series of 1-(2-hydroxybenzoyl)-thiosemicarbazides inhibitors of D-Ala-D-Ala ligase (Ddl) were designed and synthesized in order to target resistant strains of bacteria. Among these, the 4-(3,4-dichlorophenyl)-1-(2-hydroxybenzoyl)-3-thiosemicarbazide 29 was identified as a potent Ddl inhibitor with activity in the micromolar range. This compound, possessing strong antimicrobial activity including against multidrug resistant strains, was proven to act through a bactericidal mechanism and demonstrated very low cytotoxicity on THP-1 human monocytic cell line. Inhibition of Ddl activity by 29 was confirmed in bacterio using UPLC-MS/MS by demonstrating an increase in D-Ala intracellular pools accompanied by a commensurate decrease in D-Ala-D-Ala. Further structure-activity relationships (SARs) studies provided evidence that the hydroxyl substituent in the 2-position (R1) of the benzoylthiosemicarbazide scaffold is essential for the enzymatic inhibition. This work thus highlights the 1-(2-hydroxybenzoyl)-thiosemicarbazide motif as a very promising tool for the development of novel antibacterial compounds acting through an interesting mechanism of action and low cytotoxicity.
Ameryckx, Alice,Thabault, Léopold,Pochet, Lionel,Leimanis, Serge,Poupaert, Jacques H.,Wouters, Johan,Joris, Bernard,Van Bambeke, Fran?oise,Frédérick, Rapha?l
supporting information
p. 324 - 338
(2018/10/15)

Synthesis, structural studies and biological activities of three new 2-(pentadecylthio)-5-aryl-1,3,4-oxadiazoles
1,3,4-Oxadiazoles are important class of heterocyclic compounds, with diverse biological applications. In this study, the synthesis of three different 1,3,4-oxadiazoles bearing pentadecyl moiety is reported. All compounds were synthesized with significant (70–82%) yields, characterized by using different spectroanalytical techniques such as UV–vis., FT-IR, NMR (1H and 13C), and finally structures were confirmed unequivocally by single crystal X-ray diffraction analysis. Quantum chemical studies by using GAUSSIAN software at DFT/B3LYP/6-31G (d, p) level of theory have been exercised to compare and validate the spectroscopic and X-ray results. Frontier molecular orbitals (FMOs) analysis of all compounds was performed by utilizing optimized geometries and gave the idea about kinetic stability and reactivity. Molecular electrostatic potential (MEP) analysis indicated the regions for electrophilic as well as nucleophilic attack. Compounds were also screened to check their antibacterial and antifungal potential.
Ahmed, Muhammad Naeem,Yasin, Khawaja Ansar,Hameed, Shahid,Ayub, Khurshid,Haq, Ihsan-ul,Tahir, M. Nawaz,Mahmood, Tariq
p. 50 - 59
(2016/09/28)

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)

Asymmetric Synthesis and Antitumor Activity of Spiro-Oxadiazole Derivatives from 1,4:3,6-Dianhydro-D-fructose
A series of spiro-oxadiazoles were synthesized from 1,4:3,6-dianhydro-D-fructose and hydrazides via a stereo- selective two-step reaction sequence. The structures of newly synthesized compounds were established by spectral analysis. The absolute configuration of compound 2a was further confirmed by single crystal X-ray analysis. All the synthesized compounds were screened for their in vitro antitumor activity, showing that these compounds have poor inhibitory activities against A549, MGC-803 tumor cells.
Xu, Wenke,Ge, Yongxun,Hou, Yu,Liu, Yingju,Hua, Yingchun,Han, Weiwei,Qin, Zhiyan,Liu, Fengwu
p. 1437 - 144
(2017/10/06)

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 molecular modelling studies of phenyl linked oxadiazole-phenylhydrazone hybrids as potent antileishmanial agents
Molecular hybridization yielded phenyl linked oxadiazole-benzohydrazones hybrids 6–35 and were evaluated for their antileishmanial potentials. Compound 10, a 3,4-dihydroxy analog with IC50value of 0.95 ± 0.01 μM, was found to be the most potent antileishmanial agent (7 times more active) than the standard drug pentamidine (IC50= 7.02 ± 0.09 μM). The current series 6–35 conceded in the identification of thirteen (13) potent antileishmanial compounds with the IC50values ranging between 0.95 ± 0.01–78.6 ± 1.78 μM. Molecular docking analysis against pteridine reductase (PTR1) were also performed to probe the mode of action. Selectivity index showed that compounds with higher number of hydroxyl groups have low selectivity index. Theoretical stereochemical assignment was also done for certain derivatives by using density functional calculations.
Taha, Muhammad,Ismail, Nor Hadiani,Imran, Syahrul,Anouar, El Hassane,Selvaraj, Manikandan,Jamil, Waqas,Ali, Muhammad,Kashif, Syed Muhammad,Rahim, Fazal,Khan, Khalid Mohammed,Adenan, Mohd Ilham
p. 1021 - 1033
(2016/12/26)

New highly selective turn-on fluorescence receptor for the detection of copper (II)
Three new receptors (1a–c) bearing a p-dimethylaminobenzamide fluorophore have been synthesized and evaluated in terms of their fluoroionophoric properties towards various metal ions. Notably, receptors 1a and 1c exhibited dramatic fluorescent enhancement towards Cu2?+ in acetonitrile. Subsequent investigations revealed that the highly selective behavior of these receptors towards Cu2?+ could be attributed to the Cu2?+-mediated oxidative cyclization of these compounds to the corresponding 1,3,4-oxadiazoles. Solvent effects and quantum calculations indicated that 1a and 1c both possessed an intramolecular charge transfer channel, which could be obstructed by the oxidative cyclization of these receptors. Receptor 1a was successfully applied to the determination of the Cu2?+ in drug sample with a low detection limit of 2.2?×?10??8?mol?L??1.
Nan, Qian,Rong, Pu,Jiang, Yunbao,Yang, Rui
p. 307 - 315
(2016/12/18)

Facile synthesis, biological evaluation and molecular docking studies of novel substituted azole derivatives
In this study, we synthesized the series of novel azole derivatives and evaluated for enzyme inhibition assays, corresponding kinetic analysis and molecular modeling. Among the investigated bioassays, the oxadiazole derivatives 4a-k were found potent α-glucosidase inhibitors while the Schiff base derivatives 7a-k exhibited considerable potential toward urease inhibition. The inhibition kinetics for the most active compounds were analyzed by the Lineweaver–Burk plots to investigate the possible binding modes of the synthesized compounds toward the tested proteins. Moreover, the detailed docking studies were performed on the synthesized library of 4a-k and 7a-k to study the molecular interaction and binding mode in the active site of the modeled yeast α-glucosidase and Jack Bean Urease, respectively. It could be inferred from docking results that theoretical studies are in close agreement to that of the experimental results. The structure of one of the compound 7k was characterized by the single crystal X-ray diffraction analysis in order to find out the predominant conformation of the molecules.
Rafiq, Muhammad,Saleem, Muhammad,Jabeen, Farukh,Hanif, Muhammad,Seo, Sung-Yum,Kang, Sung Kwon,Lee, Ki Hwan
p. 177 - 191
(2017/03/15)

Synthesis of novel 5-(aroylhydrazinocarbonyl)escitalopram as cholinesterase inhibitors
A novel series of 5-(aroylhydrazinocarbonyl)escitalopram (58–84) have been designed, synthesized and tested for their inhibitory potential against cholinesterases. 3-Chlorobenzoyl- (71) was found to be the most potent compound of this series having IC50 1.80 ± 0.11 μM for acetylcholinesterase (AChE) inhibition. For the butyrylcholinesterase (BChE) inhibition, 2-bromobenzoyl- (76) was the most active compound of the series with IC50 2.11 ± 0.31 μM. Structure-activity relationship illustrated that mild electron donating groups enhanced enzyme inhibition while electron withdrawing groups reduced the inhibition except o-NO2. However, size and position of the substituents affected enzyme inhibitions.. In docking study of AChE, the ligands 71, 72 and 76 showed the scores of 5874, 5756 and 5666 and ACE of ?64.92,-203.25 and ?140.29 kcal/mol, respectively. In case of BChE, ligands 71, 76 and 81 depicted high scores 6016, 6150 and 5994 with ACE values ?170.91, ?256.84 and ?235.97 kcal/mol, respectively.
Nisa, Mehr-un,Munawar, Munawar A.,Iqbal, Amber,Ahmed, Asrar,Ashraf, Muhammad,Gardener, Qurra-tul-Ann A.,Khan, Misbahul A.
supporting information
p. 396 - 406
(2017/07/10)

Synthesis and antiviral activity of novel thioether derivatives containing 1,3,4-oxadiazole/thiadiazole and emodin moieties
A series of novel thioether derivatives containing 1,3,4-oxadiazole/thiadiazole and emodin moieties were designed and synthesized. The structures of the target compounds were confirmed by 1H NMR, 13C NMR, Infrared, and elemental analysis. The results of bioactivity analysis showed that most of the target compounds exhibited moderate to good antiviral activity against tobacco mosaic virus at a concentration of 500 mg/L. Especially, among the title compounds, Y2, Y8, and Y10 possessed appreciable curative activity in vivo, with inhibition rates of 50.51, 52.08, and 54.62%, respectively, which were similar to that of Ningnanmycin (53.40%).
Dong, Liangrun,Song, Baojing,Wu, Jian,Wu, Zengxue,Zhu, Yunying,Chen, Xuewen,Hu, Deyu
p. 904 - 907
(2016/07/06)

Synthesis of 2-(2-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole derivatives and evaluation of their antiglycation potential
In the search of potent antidiabetic drug, we synthesized 1-25 2-(2-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole derivatives. First, we synthesized 2-methoxybenzohydrazide from methyl 2-methoxybenzoate which was treated with different arylaldehydes to afford 1-25 compounds. The synthesized compounds were evaluated for antiglycation activity. We found that 1-6 and 8 showed potent activity ranging from 160.2 to 290.17 μM better than standard drug rutin (IC50 = 295.09 ± 1.04 μM). All the synthesized compounds were characterized by different spectroscopy methods. These compounds can further be studied to develop lead antidiabetic compounds.
Taha, Muhammad,Ismail, Nor Hadiani,Jamil, Waqas,Imran, Syahrul,Rahim, Fazal,Kashif, Syed Muhammad,Zulkefeli, Mohd
p. 225 - 234
(2016/01/25)

Antiurease, antiphosphodiesterase and antiglycation studies of Pd(II) complexes with monodentate hydrazides
The present study was aimed to synthesize and characterize a series of Pd(II)-benzohydrazide complexes with subsequent high throughput screening to seek their effects as enzyme inhibitors and antiglycating agents. Based on complete characterization via elemental (CHN, Pd) analysis, physical (conductivity, magnetic moment) measurements and spectral (FT-IR, 1H-NMR, 13C-NMR) techniques, all Pd(II) complexes were identified as diamagnetic, neutral and orienting in trans square planar geometry with general formula [PdL2Cl2]. The benzohydrazide (L) in these complexes depicts monodentate behavior, providing terminal amino nitrogen as a donor atom. Compared to inactive precursors (free benzohydrazides and Pd2+), almost all Pd(II) complexes showed in vitro antiglycation activity, illustrating the potential role of resulting complexes in the suppression of diabetes and related disorders. The presence of free carbonyl group in complexes has been recognized as possible cause of antiglycation. This study also indicated Pd(II) compounds as far more superior inhibitors of urease and phosphodiesterase-I than parent ligands; many of them exhibited inhibitions equivalent or even greater than the standard inhibitors (thiourea, urease; EDTA, phosphodiesterase), which shows their potential use in future in the control of peptic ulcer and arthritis, respectively. The structure activity relationship (SAR) study demonstrated that complexation, steric hindrance, position of substituents, electron density around metal centre, hydrogen bonding and coordination mode of complexed ligands play prime role in modulating the biological activities of complexes.
Qurrat-Ul-Ain,Rasheed, Saima,Mahroof-Tahir, Mohammad,Ashiq, Uzma,Jamal, Rifat Ara,Khurshid, Sumaira,Mustafa, Sana
p. 864 - 881
(2016/11/21)

COMPOUND HAVING ZNF143 INHIBITORY ACTIVITY AND USE THEREOF
PROBLEM TO BE SOLVED: To provide a compound having a ZNF143 inhibitory activity as well as to provide a ZNF143 inhibitory agent and pharmaceutical composition containing the same. SOLUTION: Provided is a compound represented by formula (I) or a salt thereof as well as a ZNF143 inhibitory agent containing the same and a pharmaceutical composition having the same as an active ingredient. A-B-C-D (I)[A is H, a methyl group, a naphthyl group, a phenyl group or a nitrogen-containing heterocyclic ring; B is as shown below, and C is an amide bond or a heteroaromatic ring containing N and O; D is a substituted/unsubstituted phenyl group or a monocyclic heteroaromatic ring containing N or S; and C and D are both fused heterocyclic ring or the like optionally having a substituent group.]. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2016,JPOandINPIT
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(2016/10/27)

Synthesis of novel triazoles and a tetrazole of escitalopram as cholinesterase inhibitors
A novel serie of escitalopram triazoles (60-88) and a tetrazole (89) have been synthesized and subjected to a study to establish the inhibitory potential of these compounds toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Some selectivity in inhibition has been observed. The 4-chlorophenyl- (75, IC50, 6.71 ± 0.25 μM) and 2-methylphenyl- (70, IC50, 9.52 ± 0.23 μM) escitalopram triazole derivatives depicted high AChE inhibition, while 2-fluorophenyl- (76, IC50 = 4.52 ± 0.17 μM) and 4-fluorophenyl- (78, IC50 = 5.31 ± 0.43 μM) have found to be excellent BChE inhibitors. It has also been observed that ortho, meta and para substituted electron donating groups increase the inhibition, while electron withdrawing groups reduce the inhibition. Docking analyses of inhibitors with AChE have depicted the binding energies for 70 and 75 as ΔGbind -6.42 and -6.93 kcal/mol, respectively, while ligands 76 and 78 have shown the binding affinity ΔGbind -9.04 and -8.51 kcal/mol, respectively, for BChE.
Mehr-Un-Nisa,Munawar, Munawar A.,Chattha, Fauzia A.,Kousar, Samina,Munir, Jawaria,Ismail, Tayaba,Ashraf, Muhammad,Khan, Misbahul A.
supporting information
p. 6014 - 6024
(2015/11/11)

Studies on chemistry, spectroscopy and antioxidant activities of chromium(III)-hydrazide complexes
Acid hydrazides are vital chemical entities due to their biological activities. Upon complexation with certain metal ions, their biological activities are known to be positively enhanced. The present work describes the synthesis of Cr(III)-hydrazide complexes, and their structural, spectroscopic and antioxidant properties to reveal their chemistry and biochemistry. Physical (magnetic moment, conductivity measurements), analytical (C, H, N and Cr analysis) and spectral (EI-Mass, FTIR) techniques are used for the characterization of synthesized compounds. All Cr(III)-hydrazide complexes exhibit octahedral geometry with general formula [Cr(L)2(H2O)2]Cl3. In these complexes, the hydrazide ligands are coordinated via carbonyl oxygen and terminal amino nitrogen in a bidentate fashion. All Cr(III)-hydrazide complexes were screened for in vitro diphenyldipicryl hydrazine (DPPH), superoxide dismutase and nitric oxide radical scavenging activities. Majority of the Cr(III)-hydrazide complexes were found to be more potent scavengers than their uncoordinated hydrazide ligands. This study demonstrates an interesting structure-activity relationship (SAR) which is presented here.
Shamshad, Bushra,Jamal, Rifat A.,Ashiqa, Uzma,Mahrooof-Tahirb, Mohammad,Shaikha, Zara,Sultana, Sadaf,Khanc, Khalid M.
p. 798 - 806
(2015/12/01)

Ultrasound-assisted, one-pot, three-component synthesis and antibacterial activities of novel indole derivatives containing 1,3,4-oxadiazole and 1,2,4-triazole moieties
Thirteen novel indole derivatives were efficiently synthesized through ultrasound irradiation by using 4-amino-5-(1H-indol-3-yl)-4H-[1,2,4]triazole-3-thiol (8) and 2-mercapto-5-substituted-1,3,4-oxadiazoles (5a-m). Compared with conventional and microwave methods, yields increased to 82-93%, and reaction times decreased to 15-35 min. The structures of these novel compounds were characterized by spectral data and elemental analysis. Two out of the synthesized compounds (10f and 10l) exhibited excellent activity against Staphylococcus aureus and Escherichia coli, and thus warrant further research.
Shi, Zhichuan,Zhao, Zhigang,Huang, Meiwei,Fu, Xiaolin
p. 1320 - 1327
(2015/12/11)

Synthesis and evaluation of novel azoles as potent antifungal agents
Using a rational approach to the design of antifungal agents, a series of azole agents with 1,3,4-oxadiazole side chains were designed and synthesized. The results of preliminary in vitro antifungal tests with eight human pathogenic compounds showed that all of the title compounds exhibited excellent activities against all of the tested fungi except Aspergillus fumigatus. Compounds 11e and 11f were found to be the most effective, with a minimum inhibitory concentration of 0.0039 μg/mL, followed by voriconazole, which has a MIC of 0.0625 μg/mL. The 1,3,4-oxadiazole side chain is not the major contributor but plays a role in eliciting the observed antifungal activity.
Li, Liangjing,Ding, Hao,Wang, Baogang,Yu, Shichong,Zou, Yan,Chai, Xiaoyun,Wu, Qiuye
supporting information
p. 192 - 194
(2014/01/17)

Synthesis, structure, and catalytic property of a mononuclear dioxomolybdenum(VI) complex containing MoON core
Reaction of molybdenyl(IV) oxide bis(2,4-pentanedionate) with N'-(3-ethoxy-2-hydroxybenzylidene)-2-methoxybenzohydrazide in methanol affords a mononuclear dioxomolybdenum(VI) complex containing MoO5N basic core. The complex has been characterized by various physicochemical techniques (IR and elemental analysis), and single crystal X-ray diffraction. X-ray crystal structure determination reveals that the complex crystallizes as monoclinic space group P21/c, with unit cell dimensions a = 9.251(1), b = 11.910(2), c = 17.636(3) A, β = 103.220(2)°, V = 1891.7(5) A3, Z = 4, R 1 = 0.0693, wR 2 = 0.1691. The Mo atom in the complex is octahedrally coordinated, with the tridentate ONO ligand occupying the meridional sites. Thermal stability analysis was performed. The complex shows high catalytic property for the oxidation of various olefins.
Wang
p. 268 - 272
(2014/06/24)

Microwave-assisted synthes is of novel chiral receptors derived from deoxycholic acid and their molecular recognition properties
Under microwave irradiation (MWI), novel chiral receptors derived from deoxycholic acid were synthesized by using deoxycholic acid methyl ester as the spacer, and arylhydrazine and amino acids as the arm. Selective recognition properties of these receptors for aromatic amines and D/L-amino acids have been investigated by UV-vis spectral titration and 1H NMR spectral study. The results indicate this type of receptors can form a 1:1 supramolecular complex with an aromatic amine and a 1:2 supramolecular complex with D/L-tryptophan.
Ye, Ying,Suo, Yourui,Yang, Fang,Han, Lijuan
p. 1812 - 1814
(2015/02/19)

Acyl hydrazides and triazoles as novel inhibitors of mammalian cathepsin B and cathepsin H
In the past decade, the work on the identification of small molecular weight compounds as inhibitors of cysteine proteases has been in focus. In this direction, we here present the facile microwave assisted synthesis of some acyl hydrazides and triazoles, followed by their evaluation as protease inhibitors and inhibitory studies on cathepsin B and cathepsin H, two significant lysosomal cysteine proteases. The compounds were characterized by 1H NMR, 13C NMR, Mass and IR spectral data. The compounds which were found inhibitory to endogenous proteolysis in liver homogenate at pH 5.0 were further studied for determination of inhibition type and Ki values on purified cathepsin B and cathepsin H. The maximum inhibitory effect was exerted by 3-(3′-nitrophenyl)-5-(3′-nitrophenyl)-4-amino-1,2,4-triazoles (2c), 3-(4′-chlorophenyl)-5-(4′-chloro phenyl)-4-amino-1,2,4- triazoles (2h), 3-(3′-aminophenyl)-5-(3′-aminophenyl)-4-amino-1,2,4- triazoles (2i) and 4-methoxybenzohydrazide (1b).
Raghav, Neera,Singh, Mamta
p. 231 - 242
(2014/04/03)

Novel 1,3,4-oxadiazole thioether derivatives targeting thymidylate synthase as dual anticancer/antimicrobial agents
A series of novel 1,3,4-oxadiazole thioether derivatives (compounds 9-44) were designed and synthesized as potential inhibitors of thymidylate synthase (TS) and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 18 bearing a nitro substituent exhibited more potent in vitro anticancer activities with IC50 values of 0.7 ± 0.2, 30.0 ± 1.2, 18.3 ± 1.4 μM, respectively, which was superior to the positive control. In the further study, it was identified as the most potent inhibitor against two kinds of TS protein (for human TS and Escherichia coli TS, IC50 values: 0.62 and 0.47 μM, respectively) in the TS inhibition assay in vitro and the most potent antibacterial agents with MIC (minimum inhibitory concentrations) of 1.56-3.13 μg/mL against the tested four bacterial strains. Molecular docking and 3D-QSAR study supported that compound 18 can be selected as dual antitumor/antibacterial candidate in the future study.
Du, Qian-Ru,Li, Dong-Dong,Pi, Ya-Zhou,Li, Jing-Ran,Sun, Jian,Fang, Fei,Zhong, Wei-Qing,Gong, Hai-Bin,Zhu, Hai-Liang
p. 2286 - 2297
(2013/05/09)

Design, synthesis and biological evaluation of novel arylidine- malononitrile derivatives as non-carboxylic inhibitors of protein tyrosine phosphatase 1B
In this study, we describe the design, synthesis, biological evaluation and molecular modelling studies of novel non-carboxylic arylidine malononitrile-based molecules as Protein Tyrosine Phosphatase 1B (PTP1B) inhibitors. The synthesized derivatives were evaluated in vitro for glucose reuptake using L6 muscle cell lines and enzymatic assay against PTP1B. The biological activity results showed that the 2-methoxy substituted (14b) compound exhibited significant activity in both the assays. The unsubstituted compound (14a) also possessed comparable activity on glucose reuptake in L6 muscle cell lines and better inhibitory activity on PTP1B enzyme assays. Docking analysis was performed on the most potent compound of the series to understand the nature of interactions governing the binding of the designed molecule with the PTP1B enzyme.
Deora, Girdhar Singh,Karthikeyan, Chandrabose,Moorthy, N. S. Hari Narayana,Rathore, Vandana,Rawat, Arun K.,Tamrakar, Akhilesh K.,Srivastava,Trivedi, Piyush
p. 5344 - 5348
(2013/12/04)

Synthesis of 2-methoxybenzoylhydrazone and evaluation of their antileishmanial activity
Compounds 1-25 showed varying degree of antileishmanial activities with IC50 values ranging between 1.95 and 88.56 μM. Compounds 2, 10, and 11 (IC50 = 3.29 ± 0.07 μM, 1.95 ± 0.04 μM, and 2.49 ± 0.03 μM, respectively) were found to be more active than standard pentamidine (IC50 = 5.09 ± 0.04 μM). Compounds 7 (IC50 = 7.64 ± 0.1 μM), 8 (IC50 = 13.17 ± 0.46 μM), 18 (IC50 = 13.15 ± 0.02 μM), and 24 (IC 50 = 15.65 ± 0.41 μM) exhibited good activities. Compounds 1, 3, 4, 5, 9, 12, 15, 18, and 19 were found to be moderately active. Compounds 13, 14, 16, 17, 20-25 showed weak activities with IC50 values ranging between 57 and 88 μM.
Taha, Muhammad,Baharudin, Mohd Syukri,Ismail, Nor Hadiani,Khan, Khalid Mohammed,Jaafar, Faridahanim Mohd,Samreen,Siddiqui, Salman,Choudhary, M. Iqbal
p. 3463 - 3466
(2013/06/27)

Synthesis, spectroscopic and radical scavenging studies of palladium(II)-hydrazide complexes
In present study, a series of palladium(II) complexes with biologically active hydrazide ligands have been synthesized, characterized and screened for their antioxidant (superoxide and DPPH radical scavenging) properties. Spectral studies (FT-IR, EI-mass, 13C and 1H NMR spectroscopy) and physico-chemical measurements including elemental analysis, magnetic susceptibility and conductivity measurements represented square planar structure for all complexes. Substituted and unsubstituted benzohydrazides (1-4) have shown monodentate behavior forming complexes of general formula [PdL 2Cl2]. However, pyridine-carbohydrazides (5 and 6) were coordinated in bidentate fashion of [PdLCl2] general formula producing stable five-membered chelate ring. All palladium complexes were found to be considerably more potent inhibitors of DPPH free radical compared to free hydrazides. These complexes are even stronger DPPH scavengers than standard antioxidant propyl gallate. The complexes have also shown good superoxide scavenging ability compared to inactive free hydrazides, however complexes are weaker superoxide scavengers than ascorbic acid, a standard superoxide inhibitor. An interesting structure activity relationship has been evaluated.
Ain, Qurrat Ul,Ashiq, Uzma,Jamal, Rifat Ara,Mahrooof-Tahir, Mohammad
p. 683 - 689
(2013/11/06)