- Structure based design, synthesis, and biological evaluation of imidazole derivatives targeting dihydropteroate synthase enzyme
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In this study, we have designed and synthesized 2-((5-acetyl-1-(phenyl)-4-methyl-1H-imidazol-2-yl)thio)-N-(4-((benzyl)oxy)phenyl) acetamide derivatives. Antimicrobial activities of all the imidazole derivatives have been examined against Gram-positive and Gram-negative bacteria and results showed that the conjugates have appreciable antibacterial activity. Besides, several analogous were evaluated for their in vitro antiresistant bacterial strains such as Extended-spectrum beta-lactamases (ESBL), Vancomycin-resistant Enterococcus (VRE), and Methicillin-resistant Staphylococcus aureus (MRSA). The SAR revealed that the 12l compound resulted in potency against all bacterial strains as well as ESBL, VRE, and MRSA strains. Lipinski's rule of five, and ADME studies were preformed for all the synthesized compounds with Staphylococcus aureus dihydropteroate synthase (saDHPS) protein (PDB ID: 6CLV) and were found standard drug-likeness properties of conjugates. Moreover, the binding mode of the ligands with the protein study has been examined by molecular docking and results are quite promising. Besides, all the analogous were tested for their in vitro antituberculosis, antimalarial, and antioxidant activity.
- Daraji, Drashti G.,Rajani, Dhanji P.,Rajani, Smita D.,Pithawala, Edwin A.,Jayanthi, Sivaraman,Patel, Hitesh D.
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- FACTOR XI ACTIVATION INHIBITORS
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The present invention provides a compound of Formula (I) and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing thromboses, embolisms, hypercoagulability or fibrotic changes. The compounds are selective Factor XI activation inhibitors.
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- Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide
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Topoisomerase II (TOP2) poisons as anticancer drugs work by trapping TOP2 cleavage complexes (TOP2cc) to generate DNA damage. Repair of such damage by tyrosyl DNA phosphodiesterase 2 (TDP2) could render cancer cells resistant to TOP2 poisons. Inhibiting TDP2, thus, represents an attractive mechanism-based chemosensitization approach. Currently known TDP2 inhibitors lack cellular potency and/or permeability. We report herein two novel subtypes of the deazaflavin TDP2 inhibitor core. By introducing an additional phenyl ring to the N-10 phenyl ring (subtype 11) or to the N-3 site of the deazaflavin scaffold (subtype 12), we have generated novel analogues with considerably improved biochemical potency and/or permeability. Importantly, many analogues of both subtypes, particularly compounds 11a, 11e, 12a, 12b, and 12h, exhibited much stronger cancer cell sensitizing effect than the best previous analogue 4a toward the treatment with etoposide, suggesting that these analogues could serve as effective cellular probes.
- Kankanala, Jayakanth,Ribeiro, Carlos J. A.,Kiselev, Evgeny,Ravji, Azhar,Williams, Jessica,Xie, Jiashu,Aihara, Hideki,Pommier, Yves,Wang, Zhengqiang
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supporting information
p. 4669 - 4682
(2019/05/17)
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- COMPOUNDS FOR CANCER CHEMOTHERAPEUTIC SENSITIZATION
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The invention provides a compound of formula (I), (II) or (III): wherein R1, R2, R3, R4 and R5 have any of the values described in the specification, as well as compositions comprising a compound of f
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Paragraph 0122
(2019/08/18)
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- Discovery of anilino-furo[2,3-d]pyrimidine derivatives as dual inhibitors of EGFR/HER2 tyrosine kinase and their anticancer activity
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Being responsible for the development of many cancer types, EGFR (Epidermal Growth Factor Receptor) and HER2 (Human Epidermal growth factor Receptor 2) were the focus of this study where a series of novel 4-anilino-furo[2,3-d]pyrimidine derivatives was designed, synthesized and biologically evaluated. Modification of the solvent accessible 5-position side chain greatly affected the in-vitro EGFR/HER2 inhibitory activity. Three derivatives bearing 5-carboxylic acid side chain, namely the 3-chloroanilino derivative (8c), the 3-bromoaniline (8d) and the lapatinib analogue (10) demonstrated the most significant submicromolar EGFR inhibition. Surprisingly, the in-vitro assay of the ester 7h and its acid analogue 10 showed a significant variation of results between the antiproliferative activity against A549 cell line (IC50 0.5 and 21.4 μM) respectively and EGFR inhibitory activity (18% and 100%) respectively, suggesting that 7h might be a prodrug for 10. This assumption was also affirmed by the in-vivo results, where the in-vivo antitumor assessment against EAC (Ehrlich Ascites Carcinoma) solid tumor model revealed that 7h and 8d (10 mg/kg dose) exhibited antitumor activity comparable to that of gefitinib at the same dose, exhibiting TGI% of 67%, 71% and 70%, respectively. This effect could be explained, at least partly, via activation of apoptosis, where 7h and 8d caused more than 2-fold increase of caspase 3 and cytochrome c expression than the control group which is comparable to that of gefitinib-treated group. Finally, 7h was the most effective apoptotic inducer, resulting in a significant elevation in annexin V–FITC-positive apoptotic cells (both early and late apoptosis) by 25 and 79-folds, respectively, compared to control, which is higher than that of gefitinib (22 and 61-folds, respectively).
- Hossam, Monia,Lasheen, Deena S.,Ismail, Nasser S.M.,Esmat, Ahmed,Mansour, Ahmed M.,Singab, Abdel Nasser B.,Abouzid, Khaled A.M.
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p. 330 - 348
(2017/12/28)
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- Discovery of N-(2-aminoethyl)-N-benzyloxyphenyl benzamides: New potent Trypanosoma brucei inhibitors
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A phenotypic screen of a compound library for antiparasitic activity on Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), led to the identification of N-(2-aminoethyl)-N-phenyl benzamides as a starting point for hit-to-lead m
- Buchynskyy, Andriy,Gillespie, J. Robert,Hulverson, Matthew A.,McQueen, Joshua,Creason, Sharon A.,Ranade, Ranae M.,Duster, Nicole A.,Gelb, Michael H.,Buckner, Frederick S.
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p. 1571 - 1584
(2017/02/26)
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- Design and Synthesis of 4-Anilinothieno[2,3-d]pyrimidine-Based Compounds as Dual EGFR/HER-2 Inhibitors
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Dual inhibition of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER-2) is an attractive cancer therapeutic approach. In this study, new series of 4-anilinothieno[2,3-d]pyrimidines were designed, synthesized, and tested as dual EGFR/HER-2 kinase inhibitors. Five compounds (8a, 8b, 8e–g) demonstrated low to submicromolar inhibition of both kinases with IC50 values of 1.2, 0.6, 0.3, 0.2, 0.4 μM and 8.2, 3.4, 1.3, 0.5, 2.7 μM for the EGFR and HER-2, respectively. Introduction of a 5,6-tetramethylene moiety into the thienopyrimidine core bearing a 4-(3-fluorobenzyloxy)-3-chloroaniline tail resulted in a favorable increase in both the EGFR and HER-2 inhibitory activities. Compound 8f (IC50 EGFR/HER-2: 0.2/0.5 μM) also exhibited significant cell growth inhibition on some specific NCI cell lines, especially ovarian, breast, non-small-cell lung cancer, and renal cancer cell lines.
- Abd El Hadi, Soha R.,Lasheen, Deena S.,Hassan, Mahmoud A.,Abouzid, Khaled A. M.
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p. 827 - 847
(2016/11/09)
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- Synthesis and biological evaluation of pentanedioic acid derivatives as farnesyltransferase inhibitors
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Structure-based virtual screening of a commercial library identified pentanedioic acid derivatives (6 and 13b) as a kind of novel scaffold farnesyltransferase inhibitors (FTIs). Chemical modifications of the lead compounds, biological assays and analysis of the structure-activity relationships (SAR) were conducted to discover more potent FTIs. Some of them displayed excellent inhibition against FTase, and among them, the most active compound 13n with an IC50 value of 0.0029 μM and SAR analysis might be helpful to the discovery of more potent FTIs. This journal is
- Yang, Liuqing,Liu, Wei,Mei, Hanbing,Zhang, Yuan,Yu, Xiaojuan,Xu, Yufang,Li, Honglin,Huang, Jin,Zhao, Zhenjiang
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p. 671 - 676
(2015/04/27)
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- Synthesis and in vitro antiproliferative activity of novel pyrazolo[3,4-d]pyrimidine derivatives
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A novel series of pyrazolo[3,4-d]pyrimidine derivatives were designed, synthesized and evaluated for their antiproliferative activity. Among the five compounds selected by NCI, compound 11a showed a distinctive pattern of selectivity on cell line panels and was further screened for a 5-log dose range, where it showed potent antiproliferative activity with median growth inhibition (GI50) equal to 1.71 μM against the CNS cancer SNB-75 cell line. The tested derivative showed remarkably the highest cell growth inhibition against non-small cell lung cancer HOP-62, CNS cancer SNB-75, breast cancer HS578T, and melanoma MALME-3M cell lines. Flow cytometric analysis revealed that compound 11a could significantly induce apoptosis in A549 cells in vitro at low micromolar concentrations. Further investigation showed that compound 11a induced significant cell cycle arrest at G0/G1 phase partly due to its ability to downregulate cyclin D1 and upregulate p27kip1 levels.
- Abdou, Nermin S.,Serya, Rabah A. T.,Esmat, Ahmed,Tolba, Mai F.,Ismail, Nasser S. M.,Abouzid, Khaled A. M.
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p. 1518 - 1534
(2015/08/18)
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- 2-Aminobenzothiazole derivatives: Search for new antifungal agents
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A new series of 6-substituted 2-aminobenzothiazole derivatives were synthesized and screened in vitro as potential antimicrobials. Almost all the compounds showed antifungal activity. In particular, compounds 1n,o, designed on the basis of molecular modeling studies, were the best of the series, showing MIC values of 4-8 μg/mL against Candida albicans, Candida parapsilosis and Candida tropicalis. None of the two compounds did show any cytotoxicity effect on human THP-1 cells.
- Catalano, Alessia,Carocci, Alessia,Defrenza, Ivana,Muraglia, Marilena,Carrieri, Antonio,Van Bambeke, Fran?oise,Rosato, Antonio,Corbo, Filomena,Franchini, Carlo
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p. 357 - 364
(2013/07/27)
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- DERIVATIVES OF PHENYL (THIO) UREA DEOXYTHYMIDINE AND USE THEREOF AS ANTIMALARIALS
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Deoxythymidine derivatives according to formula (I) are disclosed. wherein: X may be O or S; and R1, R2, R3, R4 and R5 may each be independently selected from H, halo, C1-C6 alkyl, C1-C6 haloalkyl, nitro, phenyl, heteroaryl, substituted heteroaryl wherein the substituents may be C1-C6 alkyl or C1-C6 haloalkyl, benzyl, -CH2OAr, -OR6 and six-membered ring heterocyclic groups containing 1 or more O and/or N heteroatoms wherein any N heteroatom may be C1-C6 alkyl-substituted; and R6 may be selected from C1-C6 alkyl, phenyl, six-membered ring heterocyclic groups containing at least one O heteroatom, benzyl and substituted benzyl wherein the substituents may be halo, C1-C6 alkyl or C1-C6 alkoxy; R7 may be H or C1-C6 alkyl; and the stereochemistry of the bond depicted as ? is either α or β. Such derivatives have shown good inhibitory activity against malaria-causing parasites, e.g. Plasmodium falciparum, but have shown low levels of toxicity to human cells.
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Page/Page column 22
(2013/03/26)
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- Synthesis and evaluation of α-thymidine analogues as novel antimalarials
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Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea- α-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this
- Cui, Huaqing,Carrero-Lérida, Juana,Silva, Ana P. G.,Whittingham, Jean L.,Brannigan, James A.,Ruiz-Pérez, Luis M.,Read, Kevin D.,Wilson, Keith S.,González-Pacanowska, Dolores,Gilbert, Ian H.
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supporting information
p. 10948 - 10957
(2013/03/13)
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- Synthesis of a new series of aminomethylated 5-nitro-1H-benzo [d] imidazoles, 6-nitrobenzo [d] oxazol-2(3H)-ones and 4-nitroisoindoline-1,3-diones as antileishmanial and antimicrobial agents
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4-(Chlorobenzyloxy) anilines were incorporated into 5-nitro-1H-benzo [d] imidazole, 6-nitrobenzo [d] oxazol-2(3H)-one and 4-nitroisoindoline-1,3-dione in the presence of 40% aq formaldehyde to furnish a new series of 5-nitro-1-(4-chlorobenzyloxy)-anilinomethyl-1 H-benzo [d] imidazoles /6-nitro-3-(4-(chlorobenzyloxy)-anilinomethyl)-benzo [d] oxazol-2(3H)-ones and 4-nitro-2-(4-chlorobenzyloxy)-anilinomethyl) isoindoline-1,3-diones (11-25). The structures of the compounds were established by means of elemental analysis and spectral data (IR & PMR). Compounds were screened for their antileishmanial and antimicrobial potential.
- Rastogi, Nisheeth,Kant, Padam,Sethi, Rakesh,Shukla, Sarveshwar,Harrison, Darwin Anil
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p. 149 - 152
(2013/09/23)
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