cas 17641-08-6, 2-CHLORO-N-(3-METHOXY-PHENYL)-ACETAMIDE

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An efficient, four-component reaction for the synthesis of novel carbamodithioates
A series of substituted phenylcarbamoyl methyl benzylcarbamodithioates have been synthesized using the multicomponent condition. The reaction proceeded under mild practical condition and afforded the desired products in good yields.
Sadat-Ebrahimi, Seyed Esmail,Karim, Leila,Moghimi, Setareh,Yahya-Meymandi, Azadeh,Mahdavi, Mohammad,Vosooghi, Mohsen,Foroumadi, Alireza,Shafiee, Abbas
p. 43 - 51
(2017)
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Design, synthesis and biological evaluation studies of novel small molecule ENPP1 inhibitors for cancer immunotherapy
Ecto-nucleotide pyrophosphatase/phosphodiesterases 1 (ENPP1 or NPP1), is an attractive therapeutic target for various diseases, primarily cancer and mineralization disorders. The ecto-enzyme is located on the cell surface and has been implicated in the control of extracellular levels of nucleotide, nucleoside and (di) phosphate. Recently, it has emerged as a critical phosphodiesterase that hydrolyzes cyclic 2′3′- cGAMP, the endogenous ligand for STING (STimulator of INterferon Genes). STING plays an important role in innate immunity by activating type I interferon in response to cytosolic 2′3′-cGAMP. ENPP1 negatively regulates the STING pathway and hence its inhibition makes it an attractive therapeutic target for cancer immunotherapy. Herein, we describe the design, optimization and biological evaluation studies of a series of novel non-nucleotidic thioguanine based small molecule inhibitors of ENPP1. The lead compound 43 has shown good in vitro potency, stability in SGF/SIF/PBS, selectivity, ADME properties and pharmacokinetic profile and finally potent anti-tumor response in vivo. These compounds are a good starting point for the development of potentially effective cancer immunotherapy agents.
Cyriac, Rajath,Gangar, Mukesh,Ghoshal, Ishani,Goswami, Avijit,Goyal, Sandeep,Khurana, Princy,Kulkarni, Aditya,Martis, Ashwita M.,Mukherjee, Apurba,Nagare, Yadav,Patel, Ketul V.,Raikar, Santosh,Raykar, Digambar,Paquin, Jean-Fran?ois
supporting information

(2021/12/20)

Anti-melanogenesis and anti-tyrosinase properties of aryl-substituted acetamides of phenoxy methyl triazole conjugated with thiosemicarbazide: Design, synthesis and biological evaluations
A series of aryl phenoxy methyl triazole conjugated with thiosemicarbazides were designed, synthesized, and evaluated for their tyrosinase inhibitory activities in the presence of L-dopa and L-tyrosine as substrates. All the compounds showed tyrosinase inhibition in the sub-micromolar concentration. Among the derivatives, compound 9j bearing benzyl displayed exceptionally high potency against tyrosinase with IC50 value of 0.11 μM and 0.17 μM in the presence of L-tyrosine and L-dopa as substrates which is significantly lower than that of kojic acid as the positive control with an IC50 value of 9.28 μM for L-tyrosine and 9.30 μM for L-dopa. According to Lineweaver–Burk plot, 9j demonstrated an uncompetitive type of inhibition in the kinetic assay. Also, in vitro antioxidant activities determined by DPPH assay recorded an IC50 value of 68.43 μM for 9i. The melanin content of 9j was determined on B16F10 melanoma human cells which demonstrated a significant reduction of the melanin content. Moreover, the binding energies corresponding to the same ligand as well as computer-aided drug-likeness and pharmacokinetic studies were also carried out. Compound 9j also possessed metal chelation potential correlated to its high anti-TYR activity.
Hosseinpoor, Hona,Moghadam Farid, Sara,Iraji, Aida,Askari, Sadegh,Edraki, Najmeh,Hosseini, Samanesadat,Jamshidzadeh, Akram,Larijani, Bagher,Attarroshan, Mahshid,Pirhadi, Somayeh,Mahdavi, Mohammad,Khoshneviszadeh, Mehdi
(2021/06/21)

Synthesis of novel 1,2,3-triazoles bearing 2,4 thiazolidinediones conjugates and their biological evaluation
Searching for new active molecules against M. Bovis BCG and Mycobacterium tuberculosis (MTB) H37Ra, a focused of 1,2,3-triazoles-incorporated 2,4 thiazolidinedione conjugates have been efficiently prepared via a click chemistry approach cyclocondensation of 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide (4), aryl aldehyde (5a–l), and mercapto acetic acid (6) with good to promising yields. The newly synthesized compounds were tested against drug-sensitive MTB and BCG. In particular, compounds 8g, 8h, 8j and 8l are highly potent against both the strains with IC90 values in the range of 1.20–2.70 and 1.24–2.65?μg/mL, respectively. Based on the results from the antitubercular activity, SAR for the synthesized series has been developed. Most of the active compounds were non-cytotoxic against MCF-7, HCT 116 and A549 cell lines. Most active compounds were having a higher selectively index, which suggested that these compounds were highly potent.
Kulkarni, Pravin S.,Karale, Sanjay N.,Khandebharad, Amol U.,Agrawal, Brijmohan R.,Sarda, Swapnil R.
p. 2035 - 2046
(2021/02/05)

Synthesis, biological evaluation, and structure-activity relationships of new tubulin polymerization inhibitors based on 5-amino-1,2,4-triazole scaffold
Based on our previous research, thirty new 5-amino-1H-1,2,4-triazoles possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities. Among them, compounds IIa, IIIh, and IIIm demonstrated significant antiproliferative activities against a panel of tumor cell lines, and the promising compound IIIm dose-dependently caused G2/M phase arrest in HeLa cells. Furthermore, analogue IIa exhibited the most potent tubulin polymerization inhibitory activity with an IC50 value of 9.4 μM, and molecular modeling studies revealed that IIa formed stable interactions in the colchicine-binding site of tubulin, suggesting that 5-amino-1H-1,2,4-triazole scaffold has potential for further investigation to develop novel tubulin polymerization inhibitors with anticancer activity.
Yang, Fang,Chen, Lin,Lai, Jin-Mei,Jian, Xie-Er,Lv, Dong-Xin,Yuan, Li-Li,Liu, Yu-Xia,Liang, Feng-Ting,Zheng, Xiao-Lan,Li, Xiong-Li,Wei, Li-Yuan,You, Wen-Wei,Zhao, Pei-Liang
(2021/03/06)

Highly Potent and Selective Butyrylcholinesterase Inhibitors for Cognitive Improvement and Neuroprotection
Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aβ deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aβ1-42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.
Li, Qi,Chen, Ying,Xing, Shuaishuai,Liao, Qinghong,Xiong, Baichen,Wang, Yuanyuan,Lu, Weixuan,He, Siyu,Feng, Feng,Liu, Wenyuan,Chen, Yao,Sun, Haopeng
p. 6856 - 6876
(2021/05/29)

Thiazolidinedione "magic Bullets" Simultaneously Targeting PPARγand HDACs: Design, Synthesis, and Investigations of their in Vitro and in Vivo Antitumor Effects
Monotargeting anticancer agents suffer from resistance and target nonspecificity concerns, which can be tackled with a multitargeting approach. The combined treatment with HDAC inhibitors and PPARγagonists has displayed potential antitumor effects. Based on these observations, this work involves design and synthesis of molecules that can simultaneously target PPARγand HDAC. Several out of 25 compounds inhibited HDAC4, and six compounds acted as dual-targeting agents. Compound 7i was the most potent, with activity toward PPARγEC50 = 0.245 μM and HDAC4 IC50 = 1.1 μM. Additionally, compounds 7c and 7i were cytotoxic to CCRF-CEM cells (CC50 = 2.8 and 9.6 μM, respectively), induced apoptosis, and caused DNA fragmentation. Furthermore, compound 7c modulated the expression of c-Myc, cleaved caspase-3, and caused in vivo tumor regression in CCRF-CEM tumor xenografts. Thus, this study provides a basis for the rational design of dual/multitargeting agents that could be developed further as anticancer therapeutics.
Tilekar, Kalpana,Hess, Jessica D.,Upadhyay, Neha,Bianco, Alessandra Lo,Schweipert, Markus,Laghezza, Antonio,Loiodice, Fulvio,Meyer-Almes, Franz-Josef,Aguilera, Renato J.,Lavecchia, Antonio,Ramaa
p. 6949 - 6971
(2021/06/25)

A copper-catalyzed synthesis of aryloxy-tethered symmetrical 1,2,3-triazoles as potential antifungal agents targeting 14 α-demethylase
The search for potent therapeutic agents has prompted the design and synthesis of a library of twenty-six aryloxy-tethered and amide-linked symmetrical 1,2,3-triazoles (8a-z) using a copper(i)-catalyzed click chemistry approach. All the synthesized compounds have been screened for theirin vitroantifungal activity against four different fungal strains as well as the enzymatic study for the inhibition of 14 α-demethylase enzyme. The bioactivity results show that most of the synthesized compounds were found to be better antifungal agents as compared to Miconazole. Among them, compound8ashowed the most promising antifungal activity against all the tested fungal strains. Furthermore, the enzymatic study reveals that compounds8iand8oare the most promising inhibitors of the 14 α-demethylase enzyme. In support of these results, the molecular docking study of the synthesized molecules against the sterol 14 α-demethylase (CYP51) could provide the structural basis for the antifungal activity. These compounds have also been analyzed for the ADME properties.
Deshmukh, Tejshri R.,Jadhav, Rohit G.,Khedkar, Vijay M.,Sangshetti, Jaiprakash N.,Sarkate, Aniket P.,Shingate, Bapurao B.,Tiwari, Shailee V.
supporting information
p. 13104 - 13118
(2021/08/03)

Design, synthesis and biological evaluation of novel 2,4-disubstituted quinazoline derivatives targeting H1975 cells via EGFR-PI3K signaling pathway
In order to find new and highly effective anti-tumor drugs with targeted therapeutic effects, a series of novel 4-aminoquinazoline derivatives containing N-phenylacetamide structure were designed, synthesized and evaluated for antitumor activity against four human cancer cell lines (H1975, PC-3, MDA-MB-231 and MGC-803) using MTT assay. The results showed that the compound 19e had the most potent antiproliferative activity against H1975, PC-3, MDA-MB-231 and MGC-803 cell lines. At the same time, compound 19e could significantly inhibit the colony formation and migration of H1975 cells. Compound 19e also arrested the H1975 cell cycle in the G1 phase and mediated cell apoptosis, promoted the accumulation of ROS in H1975 cells. Furthermore, compound 19e exerted antitumor effect in vitro by reducing the expression of anti-apoptotic protein Bcl-2 and increasing the pro-apoptotic protein Bax and p53. Mechanistically, compound 19e could significantly decreased the phosphorylation of EGFR and its downstream protein PI3K in H1975 cells. Which indicated that compound 19e targeted H1975 cell via interfering with EGFR-PI3K signaling pathway. Molecular docking showed that compound 19e could bind into the active pocket of EGFR. Those work suggested that compound 19e would have remarkable implications for further design of anti-tumor agents.
Chao, Gao,Dai, Honglin,Ke, Yu,Li, Erdong,Lihong, Shan,Liu, Hongmin,Liu, Limin,Si, Xiaojie,Wang, Zhengjie,Yang, Zhang,Zhang, Luye,Zhang, Qiurong,Zheng, Jiaxin
(2021/07/28)

Synthesis and Biological Evaluation of Dithiobisacetamides as Novel Urease Inhibitors
Thirty-eight disulfides containing N-arylacetamide were designed and synthesized in an effort to develop novel urease inhibitors. Biological evaluation revealed that some of the synthetic compounds exhibited strong inhibitory potency against both cell-free urease and urease in intact cell with low cytotoxicity to mammalian cells even at concentration up to 250 μM. Of note, 2,2′-dithiobis(N-(2-fluorophenyl)acetamide) (d7), 2,2′-dithiobis(N-(3,5-difluorophenyl)acetamide) (d24), and 2,2′-dithiobis(N-(3-fluorophenyl)acetamide) (d8) were here identified as the most active inhibitors with IC50 of 0.074, 0.44, and 0.81 μM, showing 32- to 355-fold higher potency than the positive control acetohydroxamic acid. These disulfides were confirmed to bind urease without covalent modification of the cysteine residue and to inhibit urease reversibly with a mixed inhibition mechanism. They also showed very good anti-Helicobacter pylori activities with d8 showing a comparable potency to the clinical used drug amoxicillin. The impressive in vitro biological profile indicated their immense potential as therapeutic agents to tackle H. pylori caused infections.
Fang, Hai-Lian,Li, Su-Ya,Li, Wei-Yi,Liu, Mei-Ling,Ouyang, Hui,Song, Wan-Qing,Xiao, Zhu-Ping,Ye, Ya-Xi,Zhu, Hai-Liang
(2021/11/13)

Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer's disease
In our overall goal to overcome the limitations associated with natural products for the management of Alzheimer's disease and to develop in-vivo active multifunctional cholinergic inhibitors, we embarked on the development of ferulic acid analogs. A systematic SAR study to improve upon the cholinesterase inhibition of ferulic acid with analogs that also had lower logP was carried out. Enzyme inhibition and kinetic studies identified compound 7a as a lead molecule with preferential acetylcholinesterase inhibition (AChE IC50 = 5.74 ± 0.13 μM; BChE IC50 = 14.05 ± 0.10 μM) compared to the parent molecule ferulic acid (% inhibition of AChE and BChE at 20 μM, 15.19 ± 0.59 and 19.73 ± 0.91, respectively). Molecular docking and dynamics studies revealed that 7a fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Asp74, Trp286, and Tyr337 in AChE and with Tyr128, Trp231, Leu286, Ala328, Phe329, and Tyr341 in BChE. Compound 7a was found to be an efficacious antioxidant in a DPPH assay (IC50 = 57.35 ± 0.27 μM), and it also was able to chelate iron. Data from atomic force microscopy images demonstrated that 7a was able to modulate aggregation of amyloid β1-42. Upon oral administration, 7a exhibited promising in-vivo activity in the scopolamine-induced AD animal model and was able to improve spatial memory in cognitive deficit mice in the Y-maze model. Analog 7a could effectively reverse the increased levels of AChE and BChE in scopolamine-treated animals and exhibited potent ex-vivo antioxidant properties. These findings suggest that 7a can act as a lead molecule for the development of naturally-inspired multifunctional molecules for the management of Alzheimer's and other neurodegenerative disorders.
Chittiboyina, Amar G.,Doerksen, Robert J.,Modi, Gyan,Nayak, Prasanta Kumar,Pandey, Amruta,Pandey, Pankaj,Priya, Khushbu,Rai, Geeta,Shankar, Gauri,Singh, Yash Pal,Tej, Gullanki Naga Venkata Charan,Vishwakarma, Swati
(2020/05/05)

Synthesis and evaluation of moxifloxacin derivatives for effects on proliferation and apoptosis of NCI-H1299 cells
Eight novel moxifloxacin (MXF) derivatives 4a-h were synthesized by functional modification of the N-5-Aza ring. Their growth inhibitory activities on human non-small lung cancer cell NCI-H1299 and A549 were evaluated by the MTT colorimetric assay. Based on the half inhibitory concentration (IC50) values, we determined that compounds 4b was the most efficacious derivative (IC50 = 2.56 ± 0.07 μM for NCI-H1299 and IC50 = 13.69 ± 0.70 μM for A549, respectively) that inhibited the proliferation of NCI-H1299 cells. Of these, Compound 4b (1 – cyclopropyl – 6 – fluoro – 8 – methoxy – 4 – oxo – 7 – ((4aS,7aS) – 1 – (2 – oxo – 2 – (p – tolylamino) ethyl) hexahydro – 1H – pyrrolo [3,4-b] pyridine – 6(2H)-yl) – 1,4 – dihydroquinoline – 3-carboxylic acid) showed good potency against the growth of NCI-H1299 cells and also selectivity on HUVEC cells (IC50 > 500 μM). The dose-response relationship of the characteristic morphological changes of NCI-H1299 cells induced by Compound 4b was confirmed by AO/EB fluorescent staining. Furthermore, Compound 4b triggered apoptosis of NCI-H1299 in a concentration-dependent manner and arrested cells in the G0/G1 phase. These data indicate that the N-(p-tolyl)propanamide functionalized N-5-Aza ring of moxifloxacin may be a promising lead compound and candidate for the development of new agents against non-small-cell lung cancer.
Yu, Fangmiao,Zhang, Zhuangwei,Li, Wei,Tian, Hengqun,Xu, Jun,Bao, Yongzhong
supporting information

(2020/04/10)

Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation
Epigenetics plays a fundamental role in cancer progression, and developing agents that regulate epigenetics is crucial for cancer management. Among Class I and Class II HDACs, HDAC8 is one of the essential epigenetic players in cancer progression. Therefore, we designed, synthesized, purified, and structurally characterized novel compounds containing N-substituted TZD (P1-P25). Cell viability assay of all compounds on leukemic cell lines (CEM, K562, and KCL22) showed the cytotoxic potential of P8, P9, P10, P12, P19, and P25. In-vitro screening of different HDACs isoforms revealed that P19 was the most potent and selective inhibitor for HDAC8 (IC50 – 9.3 μM). Thermal shift analysis (TSA) confirmed the binding of P19 to HDAC8. In-vitro screening of all compounds on the transport activity of GLUT1, GLUT4, and GLUT5 indicated that P19 inhibited GLUT1 (IC50 – 28.2 μM). P10 and P19 induced apoptotic cell death in CEM cells (55.19% and 60.97% respectively) and P19 was less cytotoxic on normal WBCs (CC50 – 104.2 μM) and human fibroblasts (HS27) (CC50 – 105.0 μM). Thus, among this novel series of TZD derivatives, compound P19 was most promising HDAC8 inhibitor and cytotoxic on leukemic cells. Thus, P19 could serve as a lead for further development of optimized molecules with enhanced selectivity and potency.
Aguilera, Renato J.,Choe, Jun-yong,Henze Macias, Luca,Hess, Jessica D.,Meyer-Almes, Franz-Josef,Mrowka, Piotr,Ramaa, C. S.,Schweipert, Markus,Tilekar, Kalpana,Upadhyay, Neha,J?nsch, Niklas
(2020/05/22)

Discovery and evaluation of new compounds targeting ribosomal protein S1 in antibiotic-resistant Mycobacterium Tuberculosis
The emergence of antibiotic-resistant Mycobacterium Tuberculosis (Mtb) infections compels new treatment strategies, of which targeting trans-translation is promising. During the trans-translation process, the ribosomal protein S1 (RpsA) plays a key role, and the Ala438 mutant is related to pyrazinamide (PZA) resistance, which shows its effects after being hydrolysed to pyrazinoic acid (POA). In this study, based on the structure of the RpsA C-terminal domain (RpsA-CTD) and POA complex, new compounds were designed. After being synthesized, the compounds were tested in vitro with saturation transfer difference (STD), fluorescence quenching titration (FQT) and chemical shift perturbation (CSP) experiments. Finally, six of the 17 new compounds have high affinity for both RpsA-CTD and its Ala438 deletion mutant. The active compounds provide new choices for targeting trans-translation in Mtb, and the analysis of the structure-activity relationships will be helpful for further structural modifications based on derivatives of 2-((hypoxanthine-2-yl)thio)acetic acid and 2-((5-hydroxylflavone-7-yl)oxy)acetamide.
Dai, Yazhuang,Guo, Chenyun,Lin, Donghai,Lin, Kejiang,Xu, Yinqiu,Xue, Xiaowen
(2020/04/20)

Development of triazolothiadiazine derivatives as highly potent tubulin polymerization inhibitors: Structure-activity relationship, in vitro and in vivo study
Based on our prior work, we reported the design, synthesis, and biological evaluation of fifty-two new triazolothiadiazine-based analogues of CA-4 and their preliminary structure-activity relationship. Among synthesized compounds, Iab was found to be the most potent derivative possessing IC50 values ranging from single-to double-digit nanomolar in vitro, and also exhibited excellent selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 μM). Further mechanistic studies revealed that Iab significantly blocked tubulin polymerization and disrupted the intracellular microtubule network of A549 cells. Moreover, Iab induced G2/M cell cycle arrest by regulation of p-cdc2 and cyclin B1 expressions, and caused cell apoptosis through up-regulating cleaved PARP and cleaved caspase-3 expressions, and down-regulating of Bcl-2. Importantly, in vivo, Iab effectively suppressed tumor growth of A549 lung cancers in a xenograft mouse model without obvious signs of toxicity, confirming its potential as a promising candidate for cancer treatment.
Ma, Weifeng,Chen, Peng,Huo, Xiansen,Ma, Yufeng,Li, Yanhong,Diao, Pengcheng,Yang, Fang,Zheng, Shengquan,Hu, Mengjin,You, Wenwei,Zhao, Peiliang
(2020/10/08)

Discovery and optimization of 3,4,5-trimethoxyphenyl substituted triazolylthioacetamides as potent tubulin polymerization inhibitors
Based on our previous research, three series of new triazolylthioacetamides possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities and inhibition of tubulin polymerization. The most promising compounds 8b and 8j demonstrated more significant antiproliferative activities against MCF-7, HeLa, and HT-29 cell lines than our lead compound 6. Moreover, analogues 8f, 8j, and 8o manifested more potent antiproliferative activities against HeLa cell line with IC50 values of 0.04, 0.05 and 0.16 μM, respectively, representing 100-, 82-, and 25-fold improvements of the activity compared to compound 6. Furthermore, the representative compound, 8j, was found to induce significant cell cycle arrest at the G2/M phase in HeLa cell lines via a concentration-dependent manner. Meanwhile, compound 8b exhibited the most potent tubulin polymerization inhibitory activity with an IC50 value of 5.9 μM, which was almost as active as that of CA-4 (IC50 = 4.2 μM). Additionally, molecular docking analysis suggested that 8b formed stable interactions in the colchicine-binding site of tubulin.
Yang, Fang,He, Cai-Ping,Diao, Peng-Cheng,Hong, Kwon Ho,Rao, Jin-Jun,Zhao, Pei-Liang
p. 22 - 27
(2018/11/23)

Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy
Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G0/G1 phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells’ ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC50 values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC50 value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC50 of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G0/G1 and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
Sonawane, Vinay,Mohd Siddique, Mohd Usman,Jadav, Surender Singh,Sinha, Barij Nayan,Jayaprakash, Venkatesan,Chaudhuri, Bhabatosh
p. 115 - 132
(2019/01/23)

CYP enzymes, expressed within live human suspension cells, are superior to widely-used microsomal enzymes in identifying potent CYP1A1/CYP1B1 inhibitors: Identification of quinazolinones as CYP1A1/CYP1B1 inhibitors that efficiently reverse B[a]P toxicity and cisplatin resistance
Microsomal cytochrome P450 (CYP) enzymes, isolated from recombinant bacterial/insect/yeast cells, are extensively used for drug metabolism studies. However, they may not always portray how a developmental drug would behave in human cells with intact intracellular transport mechanisms. This study emphasizes the usefulness of human HEK293 kidney cells, grown in ‘suspension’ for expression of CYPs, in finding potent CYP1A1/CYP1B1 inhibitors, as possible anticancer agents. With live cell-based assays, quinazolinones 9i/9b were found to be selective CYP1A1/CYP1B1 inhibitors with IC50 values of 30/21 nM, and > 150-fold selectivity over CYP2/3 enzymes, whereas they were far less active using commercially-available CYP1A1/CYP1B1 microsomal enzymes (IC50, >10/1.3–1.7 μM). Compound 9i prevented CYP1A1-mediated benzo[a]pyrene-toxicity in normal fibroblasts whereas 9b completely reversed cisplatin resistance in PC-3/prostate, COR-L23/lung, MIAPaCa-2/pancreatic and LS174T/colon cancer cells, underlining the human-cell-assays’ potential. Our results indicate that the most potent CYP1A1/CYP1B1 inhibitors would not have been identified if one had relied merely on microsomal enzymes.
Sonawane, Vinay R.,Siddique, Mohd Usman Mohd,Gatchie, Linda,Williams, Ibidapo S.,Bharate, Sandip B.,Jayaprakash, Venkatesan,Sinha, Barij N.,Chaudhuri, Bhabatosh
p. 177 - 194
(2019/02/27)

Synthesis, Antimicrobial Evaluation, and Docking Studies of Substituted Acetylphenoxymethyl-triazolyl-N-phenylacetamides
A series of molecules containing acetylphenoxymethyl, triazole, and N-phenylacetamide moieties were synthesized via the click chemistry approach. All the synthesized compounds were screened for their antimicrobial activities in vitro. The synthesized compounds 8a, 8b, 8m, and 8n showed better activities. We further performed exploratory docking studies to gain some insight regarding the molecular mechanism of antibacterial action of these compounds that could guide further structure-activity relationship (SAR) studies. We examined the interaction of the most active compound with DNA gyrase (pdb id:1KZN). Based on antimicrobial and docking studies, the compounds 8a, 8b, 8m, and 8n were identified as potential antimicrobial agents.
Phatak, Pramod S.,Sathe, Bhaurao P.,Dhumal, Sambhaji T.,Rehman, Naziya N. M. A.,Dixit, Prashant P.,Khedkar, Vijay M.,Haval, Kishan P.
(2019/06/08)

Synthesis, antimicrobial activity, and molecular docking study of formylnaphthalenyloxymethyl-triazolyl-N-phenylacetamides
In the present study, substituted formylnaphthalenyloxymethyl-triazolyl-N-phenylacetamide derivatives (6a–k) have been designed and synthesized employing click chemistry approach and evaluated for their in vitro antifungal and antibacterial activities. All the newly synthesized compounds were thoroughly characterized by 1H NMR, 13C NMR, and HRMS spectral techniques. Among the screened compounds, 6d, 6e, 6j, and 6k have shown good antifungal and antibacterial activities. Compound 6k has shown very effective antimicrobial activity. We further performed exploratory docking studies on microbial DNA gyrase to rationalize the in vitro biological data and to demonstrate the mechanism of antimicrobial activity. This is the first report to demonstrate the formylnaphthalenyloxymethyl, triazole, and N-phenylacetamide hybrids as potential antimicrobial agents.
Muluk, Mahesh B.,Dhumal, Sambhaji T.,Phatak, Pramod S.,Rehman, Naziya N. M. A.,Dixit, Prashant P.,Choudhari, Prafulla B.,Mane, Ramrao A.,Haval, Kishan P.
p. 2411 - 2418
(2019/07/31)

Identification and characterization of benzo[d]oxazol-2(3H)-one derivatives as the first potent and selective small-molecule inhibitors of chromodomain protein CDYL
Chemical probes of epigenetic ‘readers’ of histone post-translational modifications (PTMs) have become powerful tools for mechanistic and functional studies of their target proteins in physiology and pathology. However, only limited ‘reader’ probes have been developed, which restricted our understanding towards these macromolecules and their roles in cells or animals. Here, we reported a structure-guided approach to develop and characterize benzo [d]oxazol-2(3H)-one analogs as the first potent and selective small-molecule inhibitors of chromodomain Y-like (CDYL), a histone methyllysine reader protein. The binding conformation between the chromodomain of CDYL and the modified peptidomimetics was studied via molecular docking and dynamic simulations, facilitating subsequent virtual screening of tens of hits from Specs chemical library validated by SPR technique (KD values: from 271.1 μM to 5.4 μM). Further design and synthesis of 43 compounds helped to interpret the structure-activity relationship (SAR) that lead to the discovery of novel small-molecule inhibitors of CDYL. Compound D03 (KD: 0.5 μM) was discovered and showed excellent selectivity among other chromodomain proteins, including CDYL2 (>140 folds), CDY1 (no observed binding) and CBX7 (>32 folds). Moreover, we demonstrated that D03 engaged with endogenous CDYL in a dose-dependent manner, and perturbed the recruitment of CDYL onto chromatin, resulting in transcriptional derepression of its target genes. Finally, the results showed that D03 promoted the development and branching of neurodendrites by inhibiting CDYL in hippocampal and cortical cultured neurons. This study not only discovers the first selective small-molecule inhibitors of CDYL, but provids a new chemical tool to intervene the dynamic nature of bio-macromolecules involved in epigenetic mechanism.
Yang, Lixin,Liu, Yongqing,Fan, Minghua,Zhu, Guiwang,Jin, Hongwei,Liang, Jing,Liu, Zhenming,Huang, Zhuo,Zhang, Liangren
(2019/09/07)

Synthesis, bioevaluation and molecular docking study of new piperazine and amide linked dimeric 1,2,3-triazoles
In search of more potent new antitubercular agents, a library of novel piperazine tethered dimeric 1,2,3-triazoles were designed by assembling 1,2,3-triazoles and piperazine in a single molecular architectural framework. The titled compounds (3a–m) were synthesized by 1,3-dipolar cycloaddition of 1,4-di(prop-2-yn-1-yl)piperazine (1) and various azides (2a–m) using click chemistry approach with good yields. All the synthesized compounds (3a–m) have been screened for their in vitro antitubercular, antifungal and antioxidant activities against their respective strains. Among them, 3b, 3d, and 3i have revealed promising antitubercular activity against Mycobacterium tuberculosis (Mtb) H37Rv with MIC 12.5 μg/mL. Molecular docking results provided well-clustered solutions to the mode of binding for these molecules into the active site of Mtb enoyl reductase (InhA). In addition to this, most of synthesized compounds were found to have potential antifungal as well as antioxidant activity.
Deshmukh, Tejshri R.,Khare, Smita P.,Khedkar, Vijay M.,Krishna, Vagolu S.,Sangshetti, Jaiprakash N.,Shingate, Bapurao B.,Sriram, Dharmarajan
supporting information

(2019/12/03)

Synthesis, antiproliferative evaluation, and structure–activity relationships of novel triazole–isoindoline hybrids bearing 3,4,5-trimethoxyphenyl moiety
As an aspect of our ongoing research on developing novel antiproliferative agents, 31 new triazole–isoindoline hybrids bearing 3,4,5-trimethoxyphenyl moiety were synthesized and evaluated for their antiproliferative activity against four cancer cell lines (HepG2, HeLa, PC-3, and HCT116). Some compounds showed excellent potency, and compared to fluorouracil, the most promising compound 6s exhibited 5.8-, 4.3-, and 1.3- fold increase in activities against HeLa, HepG2, and PC-3 cell lines with IC50 values of 9.7, 10.7, and 16.8?μM, respectively. Moreover, structure–activity relationship studies indicated that a much shorter amide linkage and electron-withdrawing groups at phenyl ring of the acetamide fragment contribute to the antitumour activity.
Li, Qiu,Chen, Peng,Yang, Haikui,Luo, Miaolan,You, Wenwei,Zhao, Peiliang
p. 651 - 659
(2018/02/28)

Design, synthesis, and SAR of novel 2-glycinamide cyclohexyl sulfonamide derivatives against botrytis cinerea
N-(2-trifluoromethyl-4-chlorophenyl)-2-oxocyclohexyl sulfonamide (chesulfamide) is in the limelight as a novel fungicide, and has fungicidal activity against Botrytis cinerea. For exploring more novel structures, 33 new compounds were synthesized by N-alkylation and acid–amine coupling reactions with chesulfamide as the core moiety, and their structures were characterized and established by 1H-NMR, 13C-NMR, MS, and elemental analysis. The structure of (1R,2S)-2-(2-(N-(4-chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-trifluoromethylphenyl) acetamide (II-19) was defined by X-ray single crystal diffraction. The in vivo and in vitro fungicidal activities against B. cinerea were evaluated. The bioassay results of mycelial growth demonstrated that most compounds exhibited excellent inhibitory activity against B. cinerea at 50 μg mL?1, and 7 compounds showed lower EC50 values than boscalid (EC50 = 4.46 μg mL?1) against B. cinerea (CY-09). In cucumber pot experiment, the inhibitory rates of four compounds (II-4, II-5, II-12, and II-13) against B. cinerea were 90.48, 93.45, 92.86, and 91.07, which were better than cyprodinil (88.69%), the best performing of all controls. In tomato pot experiment, the control efficacy of two analogs (II-8 and II-15) were 87.98 and 87.97% at 200 μg mL?1, which were significantly higher than boscalid (78.10%). Most compounds have an excellent fungicidal effect on B. cinerea, with potential as a lead compound for developing new pesticides.
Cai, Nan,Liu, Caixiu,Feng, Zhihui,Li, Xinghai,Qi, Zhiqiu,Ji, Mingshan,Qin, Peiwen,Ahmed, Wasim,Cui, Zining
(2018/04/02)

Design, synthesis, docking study, α-glucosidase inhibition, and cytotoxic activities of acridine linked to thioacetamides as novel agents in treatment of type 2 diabetes
A novel series of acridine linked to thioacetamides 9a–o were synthesized and evaluated for their α-glucosidase inhibitory and cytotoxic activities. All the synthesized compounds exhibited excellent α-glucosidase inhibitory activity in the range of IC50 = 80.0 ± 2.0–383.1 ± 2.0 μM against yeast α-glucosidase, when compared to the standard drug acarbose (IC50 = 750.0 ± 1.5 μM). Among the synthesized compounds, 2-((6-chloro-2-methoxyacridin-9-yl)thio)-N-(p-tolyl) acetamide 9b displayed the highest α-glucosidase inhibitory activity (IC50 = 80.0 ± 2.0 μM). The in vitro cytotoxic assay of compounds 9a–o against MCF-7 cell line revealed that only the compounds 9d, 9c, and 9n exhibited cytotoxic activity. Cytotoxic compounds 9d, 9c, and 9n did not show cytotoxic activity against the normal human cell lines HDF. Kinetic study revealed that the most potent compound 9b is a competitive inhibitor with a Ki of 85 μM. Furthermore, the interaction modes of the most potent compounds 9b and 9f with α-glucosidase were evaluated through the molecular docking studies.
Mohammadi-Khanaposhtani, Maryam,Rezaei, Sepideh,Khalifeh, Reza,Imanparast, Somaye,Faramarzi, Mohammad Ali,Bahadorikhalili, Saeed,Safavi, Malihe,Bandarian, Fatemeh,Nasli Esfahani, Ensieh,Mahdavi, Mohammad,Larijani, Bagher
p. 288 - 295
(2018/07/06)

Anti-proliferative activity, molecular modeling studies and interaction with calf thymus DNA of novel ciprofloxacin analogues
Abstract: In our pursuit to expand new potential anticancer leads, a series of eighteen novel 1-cyclopropyl-6-fluoro-4-oxo-7-(4-substituted piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid analogues have been synthesized, characterized and evaluated anti-proliferative activity against five human cancer cell lines such as A549 (lung cancer), Mia Paca (pancreatic cancer), HeLa (cervical cancer), MDA MB-231 (breast cancer), MCF-7 (breast cancer) and normal embryonic kidney?cell line (HEK) were carried out using MTT assay. Few of the synthesized analogues exhibited potent anticancer activity against the cancer cell lines at a lower concentration. The synthesized compounds showed the less toxic effect on normal human embryonic kidney?cell line (HEK) compared with doxorubicin. Noticeably, compound 3o exhibited potent activity against all five cancer cell lines compared with ciprofloxacin. Further study exposed that compound 3o could competently intercalate into calf thymus DNA to form 3o-DNA complex which might block DNA replication to apply anti-proliferative activity. Docking simulation studies supported by molecular interactions with DNA type II topoisomerase. These derivates can become lead structures for the development of potential anticancer drugs. Graphical Abstract: Eighteen CP analogues were synthesized and evaluated for anti-proliferative activity. The interactions with DNA topoisomerase II were supported by molecular docking studies. 3o showed promising anticancer activity than CP against MCF7 cell line and interaction with calf thymus DNA was studied by fluorescence spectroscopy.[Figure not available: see fulltext.].
Suresh, Narva,Suresh, Amaroju,Yerramsetty, Suresh,Bhadra, Manika Pal,Alvala, Mallika,Sekhar, Kondapalli Venkata Gowri Chandra
(2018/08/24)

Side chain-functionalized aniline-derived ursolic acid derivatives as multidrug resistance reversers that block the nuclear factor-kappa B (NF-κB) pathway and cell proliferation
A series of inhibitors of NF-κB based on ursolic acid (UA) derivatives containing functionalized aniline or amide side chains were synthesized and evaluated for inhibition of NF-κB as well as their antitumor effects. These compounds exhibited significant inhibition activity toward NF-κB with IC50 values at micromolar concentrations in the NCI-H460 lung adenocarcinoma cell line. A docking study of the most active compound 5Y8 revealed key interactions between 5Y8 and the active site of NF-κB in which the functionalized amide moiety at the C-28 position and an ester group at the C-3 position were important for improving the activity. In particular, compound 5Y8 appeared to be the most potent compound against the NCI-H460 cell line, and displayed similar efficiency in drug-sensitive versus drug-resistant cancer cell lines, at least partly, by blocking the NF-κB signaling pathway and inducing apoptosis. Mechanistically, compound 5Y8 might trigger the apoptotic signaling pathway. Thus, the rational design of UA derivatives with functionalized aniline or amide side chains offers significant potential for the discovery of a new class of NF-κB inhibitors with the ability to induce apoptosis and reverse multidrug resistance in the NCI-H460 lung adenocarcinoma cell line.
Huang, Ri-Zhen,Hua, Shi-Xian,Liao, Zhi-Xin,Huang, Xiao-Chao,Wang, Heng-Shan
p. 1421 - 1434
(2017/07/25)

A convenient modified synthesis of 5-pyridinyl-1,3,4-thiadiazole-2-carboxamides
A general one-pot procedure is developed for the synthesis of 5-pyridinyl-1,3,4-thiadiazole-2-carboxamides by the reaction of pyridine carboxaldehydes with oxamic acid thiohydrazides. (Figure Presented).
Myannik,Yarovenko,Rodionova,Baryshnikova,Krayushkin
p. 316 - 325
(2017/10/16)

4-aminoacylphenoxyacetamide compound and medicine uses thereof
The invention belongs to the field of pharmaceutical chemistry, and relates to 4-aminoacylphenoxyacetamide compound shown as an I formula and medicine uses thereof, and in the formula, G, Z, R, m and n are described in the specification in detail. The compounds are capable of inhibiting sphingomyelin synthase activity, and are applicable to treat diseases caused by abnormal increase of sphingomyelin level. The invention further comprises compounds shown as the formula I structure, pharmaceutically-acceptable salts thereof, and application of pharmaceutical composition taking the compounds or salts thereof as an effective active composition to prevent and treat diseases caused by abnormal increase of sphingomyelin level. The diseases caused by abnormal increase of sphingomyelin level comprise atherosclerosis, fatty liver, obesity, II type diabetes and other metabolic syndrome.
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Paragraph 0053; 0054; 0055; 0061; 0062; 0063; 0064

(2016/10/08)

1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: Synthesis and in vitro biological evaluation
In our endeavor towards the development of effective VEGFR-2 inhibitors, three novel series of phthalazine derivatives based on 1-piperazinyl-4-arylphthalazine scaffold were synthesized. All the newly prepared phthalazines 16a-k, 18a-e and 21a-g were evaluated in vitro for their inhibitory activity against VEGFR-2. In particular, compounds 16k and 21d potently inhibited VEGFR-2 at sub-micromolar IC50 values 0.35 ± 0.03 and 0.40 ± 0.04 μM, respectively. Moreover, seventeen selected compounds 16c-e, 16g, 16h, 16j, 16k, 18c-e and 21a-g were evaluated for their in vitro anticancer activity according to US-NCI protocol, where compounds 16k and 21d proved to be the most potent anticancer agents. While, compound 16k exhibited potent broad spectrum anticancer activity with full panel GI50 (MG-MID) value of 3.62 μM, compound 21d showed high selectivity toward leukemia and prostate cancer subpanels [subpanel GI50 (MG-MID) 3.51 and 5.15 μM, respectively]. Molecular docking of compounds16k and 21d into VEGFR-2 active site was performed to explore their potential binding mode.
Abou-Seri, Sahar M.,Eldehna, Wagdy M.,Ali, Mamdouh M.,Abou El Ella, Dalal A.
p. 165 - 179
(2015/11/25)

Synthesis, biological evaluation, in silico docking, and virtual ADME studies of 2-[2-Oxo-3-(arylimino)indolin-1-yl]-N-arylacetamides as potent anti-breast cancer agents
A series of ten novel isatin analogs have been synthesized and screened for their in vitro anti-breast cancer activity against MCF-7 cell line using sulforhodamine-B assay method. All the tested compounds showed highly potent activity against MCF-7 cell line with especially four compounds exhibited demonstrative antiproliferative effects on MCF-7 breast cancer cell line compared to reference adramycin (doxorubicin) and GI 50 0.02 μM. Docking the synthesized compounds into the epidermal growth factor receptor, which is highly expressed in breast cancer, was employed to explore the possible interactions of these compounds with the receptor. Structure activity relationship as well as virtual ADME studies were carried out and a connection between activities, electronic and physicochemical properties of the target compounds was determined.
Debnath, Biplab,Ganguly, Swastika
p. 565 - 574
(2016/03/19)

Synthesis of Novel 6-Mercapto-12-phenethyl-quinazolino[3,4-a]quinazolinones
Novel 6-mercapto-12-phenethyl-quinazolino[3,4-a]quinazolinone derivatives were synthesized through a user-friendly five-step reaction starting from isatoic anhydride. All products were characterized by IR,1H-NMR,13C-NMR spectroscopy, and chemical analysis. All of them were evaluated for their in vitro cytotoxic activity against two cell lines namely MOLT-4 (human lymphoblastic leukemia) and MCF-7 (human breast adenocarcinoma).
Mohammadhosseini, Negar,Moradi, Shahram,Khoobi, Mehdi,Shafiee, Abbas
p. 1595 - 1602
(2016/09/24)

Design, synthesis and biological evaluation of novel 3-alkylsulfanyl-4-amino-1,2,4-triazole derivatives
Based on our previous work, a series of novel 3-alkylsulfanyl-4-amino-1,2,4-triazole derivatives were designed, synthesized and evaluated for their antiproliferative activities. The results indicated that some compounds possessed significant antiproliferative activities against four cancer cell lines, HepG2, HCT116, PC-3, and Hela. Particularly, the most promising compound 8d displayed 184-, 18-, and 17-fold improvement compared to fluorouracil in inhibiting HCT116, Hela and PC-3 cell proliferation with IC50values of 0.37, 2.94, and 31.31 μM, respectively. Most interestingly, the compound did not affect the normal human embryonic kidney cells, HEK-293. Moreover, mechanistic investigation showed that the representative compound 8d induced apoptosis and blocked cell cycle in G2/M phase in Hela cells in a dose-dependent manner. These findings suggest that compound 8d may have potential to be developed as a promising lead for the design of novel anticancer small-molecule drugs.
Zhao, Pei-Liang,Chen, Peng,Li, Qiu,Hu, Meng-Jin,Diao, Peng-Cheng,Pan, En-Shan,You, Wen-Wei
p. 3679 - 3683
(2016/07/21)

Synthesis and anti-leishmanial evaluation of 1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline derivatives against Leishmania infantum
In the present study, antileishmanial activity of sixteen novel series of tetrahydro-β-carboline derivatives against transgenic infrared fluorescent Leishmania infantum strain has been reported. Among these reported analogues, most of the compounds exhibited potent inhibition against both promastigote (IC50from 1.99?±?1.40 to 20.69?±?0.95?μM) and amastigote (IC50from 0.67?±?0.05 to 4.16?±?0.008?μM) forms of L.?infantum. Moreover, compound 7l, displayed most potent and selective inhibition of parasite amastigote form with IC500.67?±?0.05?μM, selectivity index >298.5 and was comparable with standard drug amphotericin B. From this study, a new class of tetrahydro-β-carboline derivatives with potent antileishmanial activity was identified and it needs further extensive study to optimize the lead molecules to win the battle against severe and neglected disease leishmaniasis.
Ashok, Penta,Chander, Subhash,Tejería, Ana,García-Calvo, Laura,Bala?a-Fouce, Rafael,Murugesan, Sankaranarayanan
p. 814 - 821
(2016/08/23)

Synthesis and biological evaluation of novel 1,3,4-thiadiazole derivatives incorporating benzisoselenazolone scaffold as potential antitumor agents
Background: Based on the biological signi-cance of benzisoselenazolone and 1,3,4-thiadiazole, a series of novel 1,3,4-thiadiazole derivatives incorporating benzisoselenazolone scaffold were designed and synthesized with ebselen as a lead compound. Methods: Meanwhile, their in vitro antitumor activities were evaluated against SMMC-7721, MCF-7 and A549 human cancer cell lines by CCK-8 assay. Results: The preliminary bioassay results demonstrated that all tested compounds 4a-q showed potent antitumor activities, and some compounds exhibited better effects than positive control ethaselen and 5-fluorouracil (5-FU) against various cancer cell lines. Furthermore, compounds 4b and 4m showed significant antitumor activities against SMMC-7721 cells with IC50 values of 1.89 and 1.89 μM, respectively. Compounds 4c and 4n displayed highly effective biological activities against MCF-7 cells with IC50 values of 2.88 and 2.28 μM, respectively. Compound 4i showed the best inhibitory effect against A549 cells with IC50 value of 1.76 μM. Conclusion: The pharmacological results suggest that the substituent groups of phenyl ring on the 1,3,4-thiadiazole are vital for modulating antitumor activities against various cancer cell lines.
Fu, Xiaoyun,Li, Sha,Jing, Fen,Wang, Xuefeng,Li, Baolin,Zhao, Jijun,Liu, Yuming,Chen, Baoquan
p. 631 - 639
(2016/10/18)

Structural Exploration of Quinazolin-4(3H)-ones as Anticonvulsants: Rational Design, Synthesis, Pharmacological Evaluation, and Molecular Docking Studies
Anticonvulsants effective against multiple seizures are of wide interest as antiepileptic drugs, especially if active against pharmaco-resistant seizures. Herein, we synthesized 16 different, rationally designed 2-((6,7-dimethoxy-4-oxo-2-phenylquinazolin-3(4H)-yl)amino)-N-(substituted phenyl)acetamides and screened for anticonvulsant activities through in vivo experiments. Compound 4d emerged as prototype with excellent anti-seizure action in mice against electroshock, chemically induced and pharmaco-resistant 6-Hz seizure models with no symptoms of neurotoxicity and hepatotoxicity (ED50 = 23.5 mg/kg, MES, mice, i.p.; ED50 = 32.6 mg/kg, scPTZ, mice, i.p.; ED50 = 45.2 mg/kg, 6-Hz, mice, i.p.; TD50 = 325.9 mg/kg, mice, i.p.). In addition, investigation of compound 4l in mice for its pharmacological profile proved it as safer anticonvulsant, devoid of the side effects such as motor dysfunction and hepatotoxicity of classical antiepileptic drugs (ED50 = 26.1 mg/kg, MES, mice, i.p.; ED50 = 79.4 mg/kg, scPTZ, mice, i.p.; TD50 = 361.2 mg/kg, mice, i.p.). We also predicted physiochemical and pharmacokinetic properties of structurally optimized quinazolin-4(3H)-ones by a computational protocol. A combination of in vivo anticonvulsant profile, ex vivo toxicity, and in silico studies suggested that the synthesized compounds may be useful as broad-spectrum anti-seizure drug candidates with favorable pharmacokinetic parameters.
Ugale, Vinod G.,Bari, Sanjay B.
p. 864 - 880
(2016/11/09)

Aralkylpiperidine (or piperazinecarboxylic) and its derivatives used for treating hypercalcemia schinzopherenia
PROBLEM TO BE SOLVED: To provide an agent for treating schizophrenia and related neuropsychiatric diseases.SOLUTION: This invention provides an aralkylpiperidine (or piperazine) derivative represented by formula (1), where A ring is a 5-7 membered heterocycle including N, with the heterocycle including a hetero atom arbitrarily selected from O, S, N; X is O, an amino group or a substituted amino group; Z is CH, N or C; Y is O, N or S; n is an integer of 1-5; and R1-R6 are H, a C1-C4 alkyl group or the like.
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Page/Page column 29

(2018/12/01)

Discovery, synthesis and biological evaluation of 2-(4-(N-phenethylsulfamoyl)phenoxy)acetamides (SAPAs) as novel sphingomyelin synthase 1 inhibitors
Sphingomyelin synthase (SMS) has been proved to be a potential drug target for the treatment of atherosclerosis. However, few SMS inhibitors have been reported. In this paper, structure-based virtual screening was performed on hSMS1. SAPA 1a was discovered as a novel SMS1 inhibitor with an IC50 value of 5.2 μM in enzymatic assay. A series of 2-(4-(N-phenethylsulfamoyl)phenoxy)acetamides (SAPAs) were synthesized and their biological activities toward SMS1 were evaluated. Among them, SAPA 1j was found to be the most potent SMS1 inhibitor with an IC50 value of 2.1 μM in in vitro assay. The molecular docking studies suggested the interaction modes of SMS1 inhibitors and PC with the active site of SMS1. Site-directed mutagenesis validated the involvement of residues Arg342 and Tyr338 in enzymatic sphingomyelin production. The discovery of SAPA derivatives as a novel class of SMS1 inhibitors would advance the development of more effective SMS1 inhibitors.
Li, Ya-Li,Qi, Xiang-Yu,Jiang, Hui,Deng, Xiao-Dong,Dong, Yan-Ping,Ding, Ting-Bo,Zhou, Lu,Men, Peng,Chu, Yong,Wang, Ren-Xiao,Jiang, Xian-Cheng,Ye, De-Yong
p. 6173 - 6184
(2015/09/15)

Design of a hydrogen peroxide-activatable agent that specifically targets cancer cells
Some cancers, like acute myeloid leukemia (AML), use reactive oxygen species to endogenously activate cell proliferation and angiogenic signaling cascades. Thus many cancers display increases in reactive oxygen like hydrogen peroxide concentrations. To translate this finding into a therapeutic strategy we designed new hydrogen peroxide-activated agents with two key molecular pharmacophores. The first pharmacophore is a peroxide-acceptor and the second is a pendant amine. The acceptor is an N-(2,5-dihydroxyphenyl)acetamide susceptible to hydrogen peroxide oxidation. We hypothesized that selectivity between AML and normal cells could be achieved by tuning the pendant amine. Synthesis and testing of fourteen compounds that differed at the pendent amine led to the identification of an agent (14) with 2 μM activity against AML cancer cells and an eleven fold-lower activity in healthy CD34+ blood stem cells. Interestingly, analysis shows that upon oxidation the pendant amine cyclizes, ejecting water, with the acceptor to give a bicyclic compound capable of reacting with nucleophiles. Preliminary mechanistic investigations show that AML cells made from addition of two oncogenes (NrasG12D and MLL-AF9) increase the ROS-status, is initially an anti-oxidant as hydrogen peroxide is consumed to activate the pro-drug, and cells respond by upregulating electrophilic defense as visualized by Western blotting of KEAP1. Thus, using this chemical approach we have obtained a simple, potent, and selective ROS-activated anti-AML agent.
Vadukoot, Anish K.,Abdulsalam, Safnas F.,Wunderlich, Mark,Pullen, Eboni D.,Landero-Figueroa, Julio,Mulloy, James C.,Merino, Eddie J.
supporting information
p. 6885 - 6892
(2015/02/02)

Structure-based design, synthesis, and biological evaluation of isatin derivatives as potential glycosyltransferase inhibitors
Peptidoglycan glycosyltransferase (PGT) has been shown to be an important pharmacological target for the inhibition of bacterial cell wall biosynthesis. Structure-based virtual screening of about 3 000 000 commercially available compounds against the crystal structure of the glycosyltransferase (GT) domain of the Staphylococcus aureus penicillin-binding protein 2 (S. aureus PBP2) resulted in identification of an isatin derivative, 2-(3-(2-carbamimidoylhydrazono)-2-oxoindolin-1-yl)-N-(m-tolyl)acetamide (4) as a novel potential GT inhibitor. A series of 4 derivatives were synthesized. Several compounds showed more active antimicrobial activity than the initial hit compound 4, in particular 2-(3-(2-carbamimidoylhydrazono)-2-oxoindolin-1-yl)-N-(3-nitrophenyl)acetamide (4l), against Gram-positive Bacillus subtilis and S. aureus with MIC values of 24 and 48 lg/mL, respectively. Saturation transfer difference (STD) NMR study revealed that there is a binding contact between 4l and the GT domain of S. aureus PBP2. Competitive STD-NMR further proved that 4l and moenomycin A bind to GT domain in a competitive manner. Molecular docking study suggests a potential binding pocket of 4l in the GT domain of S. aureus PBP2. Taken together, compound 4l would provide a new scaffold for further development of potent GT inhibitors.
Wang, Yong,Chan, Fung-Yi,Sun, Ning,Lui, Hok-Kiu,So, Pui-Kin,Yan, Siu-Cheong,Chan, Kin-Fai,Chiou, Jiachi,Chen, Sheng,Abagyan, Ruben,Leung, Yun-Chung,Wong, Kwok-Yin
p. 685 - 696
(2015/01/09)

Homologation of isocyanates with lithium carbenoids: A straightforward access to α-halomethyl- and α,α-dihalomethylamides
Treatment of widely available isocyanates with monohalolithium and dihalolithium carbenoids provides a valuable protocol for the one-pot preparation of α-halo- and α,α-dihaloacetamide derivatives. While monohalolithium carbenoids can be prepared by a smoo
Pace, Vittorio,Castoldi, Laura,Mamuye, Ashenafi Damtew,Holzer, Wolfgang
p. 2897 - 2909
(2015/01/16)

Design, synthesis, biological evaluation, and molecular modeling of coumarin-piperazine derivatives as acetylcholinesterase inhibitors
Acetylcholinesterase (AChE) is an important drug target for the treatment of Alzheimer's disease. A novel series of coumarin-piperazine derivatives were synthesized and their potency to inhibit human AChE enzyme (hAChE) was studied. All the final compounds were characterized by infrared, 1H NMR, 13C NMR, and elemental analysis. Docking experiments of the designed coumarin-piperazine derivatives were carried out in order to compare the theoretical and experimental binding affinities toward hAChE, to delineate the inhibitory mechanism. Subsequently, a structure-activity relationship (SAR) study using the molecular field method showed that the hydrophobic field and positive charge center conferred by the coumarin and piperazine moieties demonstrated an inhibitory mechanism. Among the compounds tested, 3f, 3j, and 3m were found to be the most potent inhibitors of hAChE. New coumarin-piperazine derivatives were synthesized and studied for their potency to inhibit the human acetylcholinesterase enzyme (hAChE). Docking experiments were carried out in order to compare the theoretical and experimental binding affinities toward hAChE. The hydrophobic field and positive charge center conferred by the coumarin and piperazine moieties demonstrated an inhibitory mechanism.
Modh, Rahul P.,Kumar, Sivakumar Prasanth,Jasrai, Yogesh T.,Chikhalia, Kishor H.
p. 793 - 804
(2013/12/04)

Exploring DOXP-reductoisomerase binding limits using phosphonated N-aryl and N-heteroarylcarboxamides as DXR inhibitors
DOXP-reductoisomerase (DXR) is a validated target for the development of antimalarial drugs to address the increase in resistant strains of Plasmodium falciparum. Series of aryl- and heteroarylcarbamoylphosphonic acids, their diethyl esters and disodium salts have been prepared as analogues of the potent DXR inhibitor fosmidomycin. The effects of the carboxamide N-substituents and the length of the methylene linker have been explored using in silico docking studies, saturation transfer difference NMR spectroscopy and enzyme inhibition assays using both EcDXR and PfDXR. These studies indicate an optimal linker length of two methylene units and have confirmed the importance of an additional binding pocket in the PfDXR active site. Insights into the constraints of the PfDXR binding site provide additional scope for the rational design of DXR inhibitors with increased ligand-receptor interactions.
Bodill, Taryn,Conibear, Anne C.,Mutorwa, Marius K.M.,Goble, Jessica L.,Blatch, Gregory L.,Lobb, Kevin A.,Klein, Rosalyn,Kaye, Perry T.
p. 4332 - 4341
(2013/07/27)

Addition of lithium carbenoids to isocyanates: A direct access to synthetically useful N-substituted 2-haloacetamides
The addition of lithium carbenoids to isocyanates provides a versatile access to N-substituted 2-haloacetamides: the reaction tolerates the presence of variously functionalized substituents on the nitrogen atom, including sterically demanding ones and reactive halogens. No erosion of the enantiopurity was observed in the case of optically active isocyanates. One of the substrates prepared has been employed in Charette's type chemoselective addition of a Grignard reagent to access an α-chloroketone.
Pace, Vittorio,Castoldi, Laura,Holzer, Wolfgang
supporting information
p. 8383 - 8385
(2013/09/23)

Synthesis and anticonvulsant activity of some novel 2-methyl imidazole derivatives
A novel series of ten N-(aryl)-2-(2-methyl-1H-imidazol-1-yl)acetamides (5a-j) were synthesized by reacting 2- methylimidazole (4) with the corresponding ω- chloroacetanilides (3a-j) in Dimethly Formamide and potassium carbonate. The compounds have been characterized on the basis of elemental analysis and spectral data. All the synthesized compounds were screened for their anticonvulsant activity. Among the compounds subjected to anticonvulsant activity, compounds 5a, 5b, 5d, 5f, 5g, 5h, 5i and 5j, at a dose of 100mg/kg body weight i.p. showed significant anticonvulsant activity (p0.01) as they delayed the onset of convulsions. The compounds 5a, 5d, 5h, 5i and 5j also decreased the duration of seizures significantly (p0.01 and P0.05) and the results were comparable to the diazepam treated group. Compound 5g is the most active molecule as; it increased the onset of convulsion time to nearly two fold and comparable duration of action to that of diazepam.
Mishra, Rahul,Ganguly, Swastika,Sethi, Kalyan Kumar,Mazumder, Papiya Mitra
experimental part
p. 402 - 408
(2012/07/13)

Discovery of novel N -phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis
In this paper, we describe the screening of a 14640-compound library using a novel whole mycobacteria phenotypic assay to discover inhibitors of EthR, a transcriptional repressor implicated in the innate resistance of Mycobacterium tuberculosis to the second-line antituberculosis drug ethionamide. From this screening a new chemical family of EthR inhibitors bearing an N-phenylphenoxyacetamide motif was identified. The X-ray structure of the most potent compound crystallized with EthR inspired the synthesis of a 960-member focused library. These compounds were tested in vitro using a rapid thermal shift assay on EthR to accelerate the optimization. The best compounds were synthesized on a larger scale and confirmed as potent ethionamide boosters on M. tuberculosis-infected macrophages. Finally, the cocrystallization of the best optimized analogue with EthR revealed an unexpected reorientation of the ligand in the binding pocket.
Flipo, Marion,Willand, Nicolas,Lecat-Guillet, Nathalie,Hounsou, Candide,Desroses, Matthieu,Leroux, Florence,Lens, Zoé,Villeret, Vincent,Wohlk?nig, Alexandre,Wintjens, René,Christophe, Thierry,Kyoung Jeon, Hee,Locht, Camille,Brodin, Priscille,Baulard, Alain R,Déprez, Benoit
supporting information; experimental part
p. 6391 - 6402
(2012/10/07)

Small-Molecule Choline Kinase Inhibitors as Anti-Cancer Therapeutics
Small molecule choline kinase inhibitors having the following formula: are provided herein. Also provided herein are pharmaceutical compositions containing Formula I compounds, together with methods of treating cancer, methods of inhibiting choline kinase enzymatic activity, and methods of treating tumors by administering an effective amount of a Formula I compound.
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(2011/10/31)

ARALKYL SUBSTITUTED PIPERIDINE OR PIPERAZINE DERIVATIVES AND THEIR USE FOR TREATING SCHIZOPHRENIA
The present invention discloses an aralkyl substituted piperidine or piperazine derivative and the use of the derivative in preparation of medicaments for treating schizophrenia and correlative psychoneuroses. It is shown by pharmacological tests that the derivative of the present invention has better antischizophrenic effect and less toxicity. Said derivative is a free base or salt of the compound having the following general formula.
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(2011/06/10)

Structure-Based Design, Synthesis, and Antifungal Activity of New Triazole Derivatives
A series of new antifungal triazole derivatives with phenylacetamide side chain were rational designed and synthesized on the basis of the structural information of lanosterol 14-demethylase (CYP51). In vitro antifungal activity assay indicated that several compounds showed higher activity than fluconazole. Especially, compound 8h showed excellent inhibitory activity against Candida albicans and Cryptococcus neoformans (MIC=0.0156μg/mL), suggesting that it is a promising lead for the development of novel antifungal agents. The binding mode of compound 8h was investigated by flexible molecular docking. It interacted with CACYP51 through hydrophobic and van der Waals interactions. A series of phenylacetamide-containing new azoles with good in vitro antifungal activity were rationally designed and synthesized.
Sheng, Chunquan,Che, Xiaoying,Wang, Wenya,Wang, Shengzheng,Cao, Yongbing,Yao, Jianzhong,Miao, Zhenyuan,Zhang, Wannian
scheme or table
p. 309 - 313
(2012/05/05)

Efficient synthesis of piperazinediones using potassium iodide catalysis in aqueous media
A simple and efficient synthetic approach to 1,4-disubstituted piperazine-2,5-diones was developed. A series of symmetrical 1,4-disubstituted piperazine-2,5-diones was prepared from chloroacetamides using potassium iodide catalysis in acetone/water. The structures of two products were confirmed by single crystal X-ray diffraction analysis.
Wen, Yong-Hong,Chen, Xiao-Na,Wen, Hui-Ling,Tang, Xiao-Fang
body text
p. 732 - 736
(2012/06/01)