- Nitroreductase-Mediated Release of Inhibitors of Lysine-Specific Demethylase 1 (LSD1) from Prodrugs in Transfected Acute Myeloid Leukaemia Cells
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Lysine-specific demethylase 1 (LSD1) has evolved as a promising therapeutic target for cancer treatment, especially in acute myeloid leukaemia (AML). To approach the challenge of site-specific LSD1 inhibition, we developed an enzyme-prodrug system with the bacterial nitroreductase NfsB (NTR) that was expressed in the virally transfected AML cell line THP1-NTR+. The cellular activity of the NTR was proven with a new luminescent NTR probe. We synthesised a diverse set of nitroaromatic prodrugs that by design do not affect LSD1 and are reduced by the NTR to release an active LSD1 inhibitor. The emerging side products were differentially analysed using negative controls, thereby revealing cytotoxic effects. The 2-nitroimidazolyl prodrug of a potent LSD1 inhibitor emerged as one of the best prodrug candidates with a pronounced selectivity window between wild-type and transfected THP1 cells. Our prodrugs are selectively activated and release the LSD1 inhibitor locally, proving their suitability for future targeting approaches.
- Herrlinger, Eva-Maria,Hau, Mirjam,Redhaber, Desiree Melanie,Greve, Gabriele,Willmann, Dominica,Steimle, Simon,Müller, Michael,Lübbert, Michael,Miething, Christoph Cornelius,Schüle, Roland,Jung, Manfred
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p. 2329 - 2347
(2020/05/06)
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- 2,4-Disubstituted 5-Nitroimidazoles Potent against Clostridium difficile
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Metronidazole is one of the first-line treatments for non-severe Clostridium difficile infections (CDI). However, resistance limits its use in cases of severe and complicated CDI. Structure–activity relationships previously described for the 5-nitroimidazole series have shown that functionalization at the 2- and 4-positions can impart better activity against parasites and anaerobic bacteria than metronidazole. Herein we report the synthesis of new 2,4-disubstituted 5-nitroimidazole compounds that show potent antibacterial activity against C. difficile. We used a vicarious nucleophilic substitution of hydrogen (VNS) reaction to introduce a phenylmethylsulfone at the 4-position and a unimolecular radical nucleophilic substitution (SRN1) reaction to introduce an ethylenic function at the 2-position of the 5-nitroimidazole scaffold.
- Spitz, Cédric,Mathias, Fanny,Péchiné, Séverine,Doan, Tri Hanh Dung,Innocent, Jean,Pellissier, Sylvain,Di Giorgio, Carole,Crozet, Maxime D.,Janoir, Claire,Vanelle, Patrice
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p. 561 - 569
(2019/02/13)
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- Green synthesis method of Ronidazole and deuterated derivative thereof
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The invention belongs to the technical field of chemical synthesis and discloses a green synthesis method of Ronidazole and a deuterated derivative thereof. The method comprises following steps: 4-nitroimidazole and methanol or deuterated methanol are subjected to a nitrogen methylation reaction or a nitrogen deuteration methylation reaction under the action of a catalyst, and 1-methyl-5-nitroimidazole or 1-trideuteromethyl-5-nitroimidazole is produced; the product and paraformaldehyde are subjected to a nucleophilic addition reaction, and 1-methyl-2-hydroxymethyl-5-nitroimidazole or 1-trideuteromethyl-2-hydroxymethyl-5-nitroimidazole is produced; the product of nucleophilic addition and urea are subjected to a heating reaction in the presence of an accelerant, and Ronidazole or the deuterated derivative thereof is produced. The raw materials are almost green reagents and are available and low in cost; conditions are simple, operation is easy, little pollution is produced, byproducts obtained in the three-step reaction are only water and ammonia gas, the post-processing method is simple, the product is easy to purify, and the yield is relatively ideal.
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Paragraph 0048-0050
(2019/09/17)
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- EXPANDED THERAPEUTIC POTENTIAL IN NITROHETEROARYL ANTIMICROBIALS
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Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to imidazole, thiazole, and furan derivatives and their use as therapeutic agents.
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Paragraph 0298
(2015/01/07)
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- Compounds containing 2-substituted imidazole ring for treatment against human African trypanosomiasis
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A series of compounds containing 2-substituted imidazoles has been synthesized from imidazole and tested for its biological activity against human African trypanosomiasis (HAT). The 2-substituted 5-nitroimidazoles such as fexinidazole (7a) and 1-[4-(1-methyl-5-nitro-1H-imidazol-2-ylmethoxy)-pyridin-2- yl-piperazine (9e) exhibited potent activity against T. brucei in vitro with low cytotoxicity and good solubility. The presence of the NO2 group at the 5-position of the imidazole ring in 2-substituted imidazoles is the crucial factor to inhibit T. brucei.
- Samant, Bhupesh S.,Sukhthankar, Mugdha G.
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supporting information; experimental part
p. 1015 - 1018
(2011/03/21)
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- BIOREDUCTIVELY-ACTIVATED PRODRUGS
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The present invention relates to a compound of formula (1), or a pharmaceutically acceptable salt thereof, Formula: (1); wherein: R1 is a substituted aryl or heteroaryl group bearing at least one nitro or azido group or is an optionally substituted benzoquinone, optionally substituted naphthoquinone or optionally substituted fused heterocycloquinone; R2 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, aryl or heteroaryl; and R3 is selected such that R3NH2 represents a cytotoxic nucleoside analogue or an ester or phosphate ester prodrug of a cytotoxic nucleoside analogue, with the proviso that if R1 is an aryl group then R2 is not H.
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Page/Page column 35-36
(2010/10/20)
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- Synthesis and biological activity of nitro heterocycles analogous to megazol, a trypanocidal lead
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As part of our efforts to develop new compounds aimed at the therapy of parasitic infections, we synthesized and assayed analogues of a lead compound megazol, 5-(1-methyl-5-nitro-1H-2-imidazolyl)-1,3,4-thiadiazol-2-amine, CAS no. 19622-55-0), in vitro. We first developed a new route for the synthesis of megazol. Subsequently several structural changes were introduced, including substitutions on the two rings of the basic nucleus, replacement of the thiadiazole by an oxadiazole, replacement of the nitroimidazole part by a nitrofurane or a nitrothiophene, and substitutions on the exocyclic nitrogen atom for evaluation of an improved import by the glucose or the purine transporters. Assays of the series of compounds on the protozoan parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani, as either extracellular cells or infected macrophages, indicated that megazol was more active than the derivatives. Megazol was then evaluated on primates infected with Trypanosoma brucei gambiense, including late-stage central nervous system infections in combination with suramin. Full recovery was observed in five monkeys in the study with no relapse of parasitemia within a 2 year follow-up. Because there is a lack of efficacious treatments for sleeping sickness in Africa and Chagas disease in South America, megazol is proposed as a potential alternative. The mutagenicity of this compound is at present being reevaluated, and metabolism is also under investigation prior to possible further developments.
- Chauvière, Gérard,Bouteille, Bernard,Enanga, Bertin,De Albuquerque, Cristina,Croft, Simon L.,Dumas, Michel,Périé, Jacques
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p. 427 - 440
(2007/10/03)
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- Synthesis and evaluation of nitroheterocyclic phosphoramidates as hypoxia-selective alkylating agents
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A series of novel nitroheterocyclic phosphoramidates has been prepared, and the cytotoxicity of these compounds has been evaluated in clonogenic assays against B16, wild-type and cyclophosphamide-resistant MCF-7, and HT-29 cells under aerobic conditions and HT-29 cells under hypoxic conditions. All compounds were comparable in toxicity to wild-type and resistant MCF-7 cells and were also selectively toxic to HT-29 cells under hypoxic conditions (selectivity ratios 1.7 to > 20). Analogues lacking the nitro group were not cytotoxic. Electron-withdrawing substituents increased cytotoxicity under aerobic conditions and thereby decreased hypoxic selectivity. In contrast, an electron-donating substituent markedly decreased both aerobic and hypoxic cytotoxicity but enhanced hypoxic selectivity. Chemical reduction of the nitro group resulted in rapid expulsion of the cytotoxic phosphoramide mustard. The most potent of these compounds show significant cytotoxicity under both aerobic and hypoxic conditions.
- Borch, Richard F.,Liu, Jiwen,Schmidt, James P.,Marakovits, Joseph T.,Joswig, Carolyn,Gipp, Jerry J.,Mulcahy, R. Timothy
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p. 2258 - 2265
(2007/10/03)
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- Design, synthesis and evaluation of imidazolylmethyl carbamate prodrugs of alkylating agents
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Two approaches to prodrugs of alkylating agents based on an imidazolylmethyl carbamate nucleus were explored. A 2-azido analogue (3) of the bis-carbamate carmethizole (1) displayed similar aerobic cytotoxicity to 1 in a panel of human and murine cell lines. Approaches to the 2-amino and 2- carbamoyl analogues are described. In the second approach an imidazolylmethanol was used as a 'trigger' linked via a carbamate to the alkylating agent N,N-bis(2-chlorethyl)amine (BCEA). Nitroimidazole and methylsulphinylimidazole carbamate prodrugs 6-8 were 5-20-fold less toxic than BCEA. Despite this deactivation in the prodrug form, little increase in cytotoxicity was observed under hypoxia. The data suggest that BCEA released on bioreduction is not sufficiently potent to contribute significant additional cytotoxicity. (C) 2000 Elsevier Science Ltd.
- Hay, Michael P.,Wilson, William R.,Denny, William A.
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p. 645 - 657
(2007/10/03)
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- Radical-nucleophilic Substitution (SRN1) Reactions. Part 5. Anions of Nitroimidazoles in SRN1 and Oxidative Addition Reactions
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The anions of 2- and 4(5)-nitroimidazole, and 2-methyl-4(5)-nitroimidazole, have been shown to undergo SRN1 reactions with a range of halogeno-nitroalkanes (which include p-nitrobenzyl chloride, 2-bromo- and 2-chloro-2-nitropropane, 2,2-dinitropropane, 5-bromo-5-nitro-1,3-dioxane, and 2-(bromo- and chloromethyl)-1-methyl-5-nitroimidazole to yield the corresponding N(1)-(nitroalkyl) derivatives.The anions of 2-methyl-4(5)-nitro- and 4(5)-nitro-imidazole, but not the anion of 2-nitroimidazole, underwent oxidative addition to the anion of 2-nitropropane (using potassium ferricyanide and sodium persulphate as oxidants) to yield the corresponding N(1)-(1-methyl-1-nitroethyl) derivatives.The anions of 2-methyl-4-nitro- and 4-nitro-imidazole have also been shown to act as nucleofuges in the SRN1 reactions between their 1-(1-methyl-1-nitroethyl)-derivatives and anions (which include Me2CNO2- and PhSO2-).Steric constrains, kinetic control, and the nature of the intermediate radical anions in the above reactions are discussed.
- Adebayo, Adelaide T. O. M.,Bowman, W. Russell,Salt, W. G.
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p. 2819 - 2828
(2007/10/02)
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- Isoxazole substituted nitroimidazoles
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Novel substituted nitroimidazoles are provided, for example, 2-(4,5-substituted-isoxazol-3-yl)-1-substituted-5-nitroimidazole; 2-(4,5-disubstituted-Δ2 -isoxazolin-3-yl)-1-substituted-5-nitroimidazole; or 2-(4,5-disubstituted-2-loweralkyl-isoxazolidin-3-yl)-1-substituted-5-nitroimidazole. These compounds have antibacterial and antiprotozoal activity, especially against human and animal trypanosomiasis and trichomoniasis.
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