138. The search for chemotherapeutic amidines. Part X. Substituted 4 : 4′-diamidino-αω-diphenoxyalkanes and -diphenyl ethers

Berg, S. S.; Newbery, George

doi:10.1039/jr9490000642

Cited by 43 publications

(21 citation statements)

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“…Compound 33, l,5-bis(4-amidinophenoxy)pentane diisethionate, and compound 34, l,5-bis(3-amidinophenoxy)pentane dihydrochloride dihydrate, were obtained from May & Baker, Ltd., Dagenham, England. The following chemicals were prepared by previously described methods: 4-cyano-2-iodophenol,16 2,6-dibromo-4-cyanophenol,17 2chloro-4-cyanophenol,6•16 and 2-bromo-4-cyanophenol.9, 16 The target amidino compounds were prepared from the corresponding dicyano derivatives by slight modifications of a procedure developed by Ashley et al 18 and by Berg and Newberry. 16 Analyses for all amidino derivatives were within ±0.3% of the theoretical values and were determined by either Atlantic Microlab, Inc., Atlanta, Ga., or Galbraith Laboratories, Inc., Knoxville, Tenn.…”

Section: Discussionmentioning

confidence: 99%

New aromatic diamidines with central .alpha.-oxyalkane or .alpha.,.omega.-dioxyalkane chains. Structure-activity relations for the inhibition of trypsin, pancreatic kallikrein, and thrombin and for the inhibition of the overall coagulation process

Geratz¹,

Cheng²,

Tidwell³

1975

J. Med. Chem.

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A series of omega-amidinophenylalkyl amidinophenyl ethers was synthesized and examined for inhibitory activity against trypsin, pancreatic kallikrein, and thrombin. Modifications of the compounds included lengthening of the alkane chain, variation in the position of the amidino groups, and substitution of halogen on the benzene rings. The compounds act as competitive reversible inhibitors, and many of them possess considerable potency. An outstanding trypsin inhibitor was found in 4-amidinophenylethyl 4 amidino-2-bromophenyl ether (compound 7) with a Ki value of 7.3 x 10(-8) M (pH 8.1, 37 degrees). A number of aromatic diamidines with a central dioxyalkane chain were similarly studied. Here, 1-(4-amidino-2-iodophenoxy)-5-(3-amidinophenoxy)pentane (compound 32) was a highly effective inhibitor of bovine thrombin (Ki = 1.1 x 10(-6) M), of human thrombin, and of the overall clotting process of human plasma.

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Section: Discussionmentioning

confidence: 99%

New aromatic diamidines with central .alpha.-oxyalkane or .alpha.,.omega.-dioxyalkane chains. Structure-activity relations for the inhibition of trypsin, pancreatic kallikrein, and thrombin and for the inhibition of the overall coagulation process

Geratz¹,

Cheng²,

Tidwell³

1975

J. Med. Chem.

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“…Bisnitriles 11a-21a were prepared following well established methods, including S N Ar reactions of various 4-chlorobenzonitriles (when X = S or NH), or S N 2 reactions of several 4-hydroxybenzonitriles (when X = O) (Scheme 3). [25][26][27][28][29][30][31][32][33] Anti-Pneumocystis activity Compounds 1-21 were first tested at a single high dose to screen out ineffective products. With the exception of compound 2, all studied pentamidine derivatives were effective at reducing the viability of P. carinii in vitro at 100 μg ml −1 screening concentration.…”

Section: Chemistrymentioning

confidence: 99%

Development of highly active anti-Pneumocystisbisbenzamidines: insight into the influence of selected substituents on thein vitroactivity

et al. 2017

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Here we describe the potency of 21 pentamidine analogues against the fungal pathogen, , in an ATP bioluminescent assay with toxicity profiles in 2 mammalian cell lines. Reduction of two 5-methyl-1,2,4-oxadiazole rings was applied to the synthesis of acid-labile bisamidines. Anti- activity is discussed in the context of 3 groups of compounds depending on the main structural changes of the pentamidine lead structure. The groups include: 1) 1,4-bis(methylene)piperazine derivatives ; 2) alkanediamide derivatives; 3) alkane-derived bisbenzamidines . IC values of 18 compounds were lower than the IC of pentamidine. Four bisamidines were active at nanogram concentrations. Introduction of sulfur atoms in the alkane bridge, replacement of the amidino groups with imidazoline rings, or attachment of nitro or amino groups to the benzene rings is responsible for remarkable activity of the new leading structures. The vast majority of compounds, including four highly active ones, can be classified as mild or nontoxic to host cells. These compounds show promise as candidates for new anti- agents.

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“…The method of preparation of diamidines was essentially according to the established route [45,46] which involves the preparation of dinitriles and their conversion to diamidines. Experimental details for 5 and 6 are given elsewhere [47].…”

Section: Synthesis Of Pentamidine Analoguesmentioning

confidence: 99%

Electrochemical DNA Biosensor for Testing Pentamidine and Its Analogues as Potential Chemotherapeutics

et al. 2006

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Electrochemical DNA-based biosensors are used as screening devices for a rapid evaluation of chemical compounds interacting with double helix of the nucleic acid. Pentamidine is one of minor groove binding chemotherapeutics clinically used as anti-PCP agent. Therefore, we designed, synthesized and tested some pentamidine analogues with diethyl ether linker and 1,2-diazine (pyridazine) or 1,3,5-triazine derivatives with cyanophenoxy substituent, precursors of amidine groups to establish if they can be more efficacious DNA interacting compounds than the original pentamidine drug. The tested compounds were: 1,5-bis(4-amidinophenoxy)pentane isethionate-pentamidine (1) used as template, 6-chloro-3-(4-cyanophenoxy)pyridazine (2), 4,6-dichloro-2-(4-cyanophenoxy)-1,3,5-triazine (3), 4-amidinophenol dihydrate (4), 1,5-bis(4-amidinophenoxy)-3-oxapentane dihydrochloride-g-oxapentamidine (5), 1,5-bis(N-cyclohexyl-4-amidinophenoxy)-3-oxapentane dihydrochloride (6). The results show that none of the tested analogues binds dsDNA more strongly than the original drug pentamidine (1). Compound 2 with pyridazine group interacts with the nucleic acid in a different way than the one with triazine (3) -the signals obtained using DNA-based biosensor had opposite features. Close derivatives 5 and 6 of the main drug pentamidine (1) showed a weak influence on the double-stranded nucleic acid which proves that even small changes in the structure of a molecule can strongly affect the character and properties of the above mentioned compounds in the presence of DNA. In this context atomic charge distribution in the studied molecules is also discussed.

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138. The search for chemotherapeutic amidines. Part X. Substituted 4 : 4′-diamidino-αω-diphenoxyalkanes and -diphenyl ethers

Cited by 43 publications

References 0 publications

New aromatic diamidines with central .alpha.-oxyalkane or .alpha.,.omega.-dioxyalkane chains. Structure-activity relations for the inhibition of trypsin, pancreatic kallikrein, and thrombin and for the inhibition of the overall coagulation process

New aromatic diamidines with central .alpha.-oxyalkane or .alpha.,.omega.-dioxyalkane chains. Structure-activity relations for the inhibition of trypsin, pancreatic kallikrein, and thrombin and for the inhibition of the overall coagulation process

Development of highly active anti-Pneumocystisbisbenzamidines: insight into the influence of selected substituents on thein vitroactivity

Electrochemical DNA Biosensor for Testing Pentamidine and Its Analogues as Potential Chemotherapeutics

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