The Chemistry of Imidates.

Roger, Robert; Neilson, Douglas G.

doi:10.1021/cr60210a003

Cited by 396 publications

(181 citation statements)

References 201 publications

(352 reference statements)

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“…That reaction, performed in boiling dimethyl formamide, produces the expected tricyclic molecules in good yields (e.g., compound 29 was obtained in 70% yield), provided the aromatic precursor bears a strong electron-withdrawing group in the para position. Conversion of the bisbenzonitrile derivative into the targeted bisbenzamidines was effected by the Pinner reaction (29). 1 H nuclear magnetic resonance (NMR) spectra were obtained by using a Varian Inova instrument (500 MHz), chemical shifts (␦) are given in parts per million (ppm) with tetramethylsilane (TMS) as an internal reference.…”

Section: Methodsmentioning

confidence: 99%

Highly Active Anti- Pneumocystis carinii Compounds in a Library of Novel Piperazine-Linked Bisbenzamidines and Related Compounds

Cushion

Walzer

Collins

et al. 2004

Antimicrob Agents Chemother

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Trimethoprim-sulfamethoxazole and pentamidine isethionate have been used extensively for the prophylaxis and therapy of pneumonia caused by Pneumocystis jirovecii. Problems associated with toxicity and potential emerging resistance for both therapies necessitate the development of safe and effective analogs or new treatment strategies. In the present study, a library of 36 compounds was synthesized by using the pentamidine molecule as the parent compound modified by a 1,4-piperazinediyl moiety as the central linker to restrict conformation flexibility. The compounds were evaluated for anti-Pneumocystis carinii activity in a bioluminescent ATP-driven assay. Four of the compounds were highly active, with 50% inhibitory concentration (IC 50 ) values of <0.01 g/ml; four had very marked activity (IC 50 < 0.10 g/ml); ten had marked activity (IC 50 < 1.0 g/ml); nine had moderate activity (IC 50 < 10 g/ml); one had slight activity (IC 50 ‫؍‬ 34.1 g/ml); and the remaining eight did not demonstrate activity in this assay system. The high level of activity was specifically associated with an alkyl chain length of five to six carbons attached to one of the nitrogens of the bisamidinium groups. None of the highly active compounds and only one of the very marked compounds exhibited any toxicity when evaluated in three mammalian cell lines. The strategy of substitution of 1,4-piperazine-linked bisbenzamidines produced compounds with the highest level of activity observed in the ATP assay and holds great promise for the development of efficacious anti-P. carinii therapy.Despite advances in the treatment of human immunodeficiency virus infection, Pneumocystis jirovecii pneumonia remains a leading cause of opportunistic infection and mortality in human immunodeficiency virus-infected patients. Currently available anti-Pneumocystis drugs are limited by significant problems of efficacy, toxicity, and emerging resistance (14,21,37,38). No member of the genus Pneumocystis can be maintained continuously outside the mammalian lung. Thus, drug development, as well as other aspects of investigation of this organism family, has been hindered.The effective use of pentamidine isethionate for the treatment of human Pneumocystis pneumonia was first reported in 1958 (18), and the early experience with the drug was summarized in 1967 (19). Trimethoprim-sulfamethoxazole (TMP-SMZ) later became the therapy of choice for this pneumonia due to increased efficacy and reduced toxicity (16). Despite concerted efforts focusing on modifications of the dihydrofolate reductase and dihydropteroate inhibitor portions of TMP-SMZ and the diamidine structure of pentamidine, no compound with increased anti-Pneumocystis carinii properties without toxicity has emerged as a clinical drug (11). With the potential problem of emerging resistance to the sulfa component of TMP-SMZ (1, 21, 26), the significant failure rate of prophylactic pentamidine, and its limited spectrum (17) and associated toxicity (2), it is necessary to identify new therapies or modifications of ...

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Section: Methodsmentioning

confidence: 99%

Highly Active Anti- Pneumocystis carinii Compounds in a Library of Novel Piperazine-Linked Bisbenzamidines and Related Compounds

Cushion

Walzer

Collins

et al. 2004

Antimicrob Agents Chemother

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“…[41] Although imidates can be prepared by the Pinner-type reaction, some difficulties are often encountered such as low yields and limited substrate scope. [42] The replacement of an amine coupling partner by alcohols in the copper-catalyzed multicomponent reaction of sulfonyl azides and 1-alkynes allowed facile access to imidates under mild conditions (Scheme 21). [43] Both primary or secondary aliphatic alcohols and phenols readily participated in the Cu-MCR to furnish imidates in high yields.…”

Section: Imidate Synthesis Using Alcoholsmentioning

confidence: 99%

Sulfonyl and Phosphoryl Azides: Going Further Beyond the Click Realm of Alkyl and Aryl Azides

Kim

Park

Choi

et al. 2011

Chemistry An Asian Journal

223

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Whereas alkyl and aryl azides readily react with terminal alkynes to afford 1,4-disubstituted-1,2,3-triazoles in excellent yields and selectivity in the presence of a copper catalyst, sulfonyl, phosphoryl, and certain acyl azides allow additional chemistry upon ring-opening of the corresponding copper-triazole intermediates. The amazingly versatile new chemistry stems from the high reactivity of a ring-opened ketenimine intermediate, with which a wide range of nucleophiles react to give multicomponent products. Among those nucleophiles, amines, alcohols, water, and heterocyclic compounds are especially capable of being involved in this new chemistry.

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“…The separated salts are then reacted with amines to generate the amidines shown in Scheme 4. 13,14 This method can be also considered as the most widely used procedure for the preparation of unsubstituted amidines. The direct synthesis of amidines from nitriles and amines can only be achieved if nitriles are substituted by electron-withdrawing groups.…”

Section: Amidines From Nitrilesmentioning

confidence: 99%