- Selective Late-Stage Sulfonyl Chloride Formation from Sulfonamides Enabled by Pyry-BF4
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Reported here is a simple and practical functionalization of primary sulfonamides, by means of a pyrylium salt (Pyry-BF4), with nucleophiles. This simple reagent activates the poorly nucleophilic NH2 group in a sulfonamide, enabling the formation of one of the best electrophiles in organic synthesis: a sulfonyl chloride. Because of the variety of primary sulfonamides in pharmaceutical contexts, special attention has been focused on the direct conversion of densely functionalized primary sulfonamides by a late-stage formation of the corresponding sulfonyl chloride. A variety of nucleophiles could be engaged in this transformation, thus permitting the synthesis of complex sulfonamides, sulfonates, sulfides, sulfonyl fluorides, and sulfonic acids. The mild reaction conditions and the high selectivity of Pyry-BF4 towards NH2 groups permit the formation of sulfonyl chlorides in a late-stage fashion, tolerating a preponderance of sensitive functionalities.
- Gómez-Palomino, Alejandro,Cornella, Josep
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supporting information
p. 18235 - 18239
(2019/11/13)
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- Synthesis and evaluation of oryzalin analogs against Toxoplasma gondii
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The synthesis and evaluation of 20 dinitroanilines and related compounds against the obligate intracellular parasite Toxoplasma gondii is reported. Using in vitro cultures of parasites in human fibroblasts, we determined that most of these compounds selectively disrupted Toxoplasma microtubules, and several displayed sub-micromolar potency against the parasite. The most potent compound was N1,N1-dipropyl-2,6-dinitro-4-(trifluoromethyl)-1,3- benzenediamine (18b), which displayed an IC50 value of 36 nM against intracellular T. gondii. Based on these data and another recent report [Ma, C.; Tran, J.; Gu, F.; Ochoa, R.; Li, C.; Sept, D.; Werbovetz, K.; Morrissette, N. Antimicrob. Agents Chemother. 2010, 54, 1453], an antimitotic structure-activity relationship for dinitroanilines versus Toxoplasma is presented.
- Endeshaw, Molla M.,Li, Catherine,Leon, Jessica De,Yao, Ni,Latibeaudiere, Kirk,Premalatha, Kokku,Morrissette, Naomi,Werbovetz, Karl A.
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scheme or table
p. 5179 - 5183
(2010/10/03)
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- Antikinetoplastid antimitotic activity and metabolic stability of dinitroaniline sulfonamides and benzamides
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N1-Phenyl-3,5-dinitro-N4,N4-di-n-propylsulfanilamide (1) and N1-phenyl-3,5-dinitro-N4,N4-di-n-butylsulfanilamide (2) show potent in vitro antimitotic activity against kinetoplastid parasites but display poor in vivo activity. Seventeen new dinitroaniline sulfonamide and eleven new benzamide analogs of these leads are reported here. Nine of the sulfonamides display in vitro IC50 values under 500 nM against African trypanosomes, and the most active antikinetoplastid compounds also inhibit the in vitro assembly of purified leishmanial tubulin with potencies similar to that of 2. While several of the potent compounds are rapidly degraded by rat liver S9 fractions in vitro, N1-(3-hydroxy)phenyl-3,5-dinitro-N4,N4-di-n-butylsulfanilamide (21) displays an IC50 value of 260 nM against African trypanosomes in vitro and is more stable than 2 in the in vitro metabolism assay.
- George, Tesmol G.,Johnsamuel, Jayaseharan,Delfin, Dawn A.,Yakovich, Adam,Mukherjee, Mitali,Phelps, Mitch A.,Dalton, James T.,Sackett, Dan L.,Kaiser, Marcel,Brun, Reto,Werbovetz, Karl A.
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p. 5699 - 5710
(2007/10/03)
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- Synthesis and Antitubulin Activity of N1- and N 4-Substituted 3,5-Dinitro Sulfanilamides against African Trypanosomes and Leishmania
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Thirty analogues of N1-phenyl-3,5-dinitro-N4,N 4-di-n-propylsulfanilamide (GB-II-5, compound 3), a new antikinetoplastid antimitotic agent, have been synthesized and evaluated. The addition of simple functional groups to the N1 aromatic ring generally decreases antiparasitic and antimitotic potency, but placement of a dibutyl substituent at the N4 nitrogen to give N1-phenyl-3,5-dinitro-N 4,N4-di-n-butylsulfanilamide (compound 35) augments antitrypanosomal and antileishmanial activity. Compound 35 possesses IC 50 values of 0.12 and 2.6 μM against cultured T. brucei and L. donovani amastigote-like forms, surpassing the activity of compound 3 against these parasites by 3.4- and 1.9-fold, respectively. Compound 35 inhibits the assembly of leishmanial tubulin with an IC50 of 6.9 μM and displays antimitotic effects in cultured T. brucei as assessed by flow cytometry, but shows little effect on purified mammalian tubulin, and displays 100-fold selectivity for trypanosomes over two mammalian cell lines. Although 3 and 35 were not effective in initial in vivo antitrypanosomal assays, the in vitro potency and selectivity of these compounds make N 1-aryl-3,5-dinitro-N4,N4-dialkylsulfanilamides a promising new class of antikinetoplastid agents that act on parasite tubulin.
- Bhattacharya, Gautam,Herman, Johnathan,Delfín, Dawn,Salem, Manar M.,Barszcz, Todd,Mollet, Mike,Riccio, Guy,Brun, Reto,Werbovetz, Karl A.
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p. 1823 - 1832
(2007/10/03)
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- Antileishmanial dinitroaniline sulfonamides with activity against parasite tubulin.
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Novel dinitroaniline sulfonamides based on the herbicide oryzalin 3 were synthesized and evaluated for activity against the parasitic protozoan Leishmania donovani and against leishmanial tubulin, the putative antiparasitic target of oryzalin. A subset of these compounds possess more activity against both Leishmania and the target protein in vitro. Compound 20 displays improved potency against leishmanial tubulin and is 13.4-fold more active against L. donovani axenic amastigotes than oryzalin.
- Bhattacharya, Gautam,Salem, Manar M,Werbovetz, Karl A
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p. 2395 - 2398
(2007/10/03)
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