New hydrazones of 5-nitro-2-furaldehyde with adamantanealkanohydrazides: synthesis and in vitro trypanocidal activity

Abstract

A range of hydrazones of 5-nitro-2-furaldehyde with adamantane alkanohydrazides was synthesized and their trypanocidal activity was evaluated.

Synthesis and Evaluation of Nifurtimox–Adamantane Adducts with Trypanocidal Activity

“…[3] Fexinidazole, which was recommendedb yt he European Medicines Agency in November 2018, is as uccessful example of the collaboration betweent he Drugs for Neglected Diseases initiative (DNDi)a nd the pharmaceuticalchemistry sector. [6] We have been interested in adamantane chemistry [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] and have prepared al arge number of analogues in an attemptt o exploit adamantane's role in bioactivity.W ep repared as eries of adamantane carbohydrazones [22] and showedt hat these derivatives are very potent trypanocidals. Following this work, we now describe the preparation of as eries of phenylhydrazone analogues, 1a-d and 2a-d,w hich in general have very promising antitrypanosomal activity.T he new derivatives share common structural features with nifurtimoxa nd also contain a phenyl-substituteda damantane ring.…”

“…The spacerb etween the phenyl ring and the carbonyl group appears to have as ignificant impact on activity and cytotoxicity.I ts eems that the present structuralm odification involving the insertion of a phenylr ing between the adamantane core and the hydrazone side chain hasi mproved the pharmacological characteristics of the new molecules,i nt erms of activity and toxicity,r elative to the adamantane carbohydrazones (IV), we previously reported. [22] Direct attachment of the hydrazone linker to the phenylr ing decreased the potency,a nd ao ne-or two-methylene spacer wasa ssociated with enhanced activity.A dducts 1b, 1c and 2b, 2c exhibited highert rypanocidal activity than analogues 1a and 2a,r espectively.C onversely,r eplacement of one methylene unit with an oxygen atom had ad etrimental impact on activity.T he position of substitution on the adamantane core (C1, C2) influenced cytotoxicity,a nd the C1-substituted hydrazones 1b (SI Tb = 770) and 1c (SI Tb = 520) were found to be more selectivet han the corresponding C2-substituted adducts 2b (SI Tb = 235) and 2c (SI Tb = 215). The same pattern was also observed in the T. cruzi results.…”

“…The most active adduct, with the best selectivity,was found to be phenylacetoxy hydrazone 1b (EC 50 = 11 AE 0.9 nm,S I Tb = 770). [22] In conclusion, the new nifurtimox-adamantane hydrazone adducts show higher trypanocidal potencyt han both the [28] [a] EC 50 and EC 90 :c oncentrationst hat inhibit growth by 50 and 90 %, respectively. [22] Direct attachment of the hydrazone linker to the phenylr ing decreased the potency,a nd ao ne-or two-methylene spacer wasa ssociated with enhanced activity.A dducts 1b, 1c and 2b, 2c exhibited highert rypanocidal activity than analogues 1a and 2a,r espectively.C onversely,r eplacement of one methylene unit with an oxygen atom had ad etrimental impact on activity.T he position of substitution on the adamantane core (C1, C2) influenced cytotoxicity,a nd the C1-substituted hydrazones 1b (SI Tb = 770) and 1c (SI Tb = 520) were found to be more selectivet han the corresponding C2-substituted adducts 2b (SI Tb = 235) and 2c (SI Tb = 215).…”

“…[5] This has led the World Health Organization (WHO) to coordinate public sector and private partnerships as part of ag lobale ffort to develop new ands afer dugs. [6] We have been interested in adamantane chemistry [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] and have prepared al arge number of analogues in an attemptt o exploit adamantane's role in bioactivity.W ep repared as eries of adamantane carbohydrazones [22] and showedt hat these derivatives are very potent trypanocidals. [6] We have been interested in adamantane chemistry [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] and have prepared al arge number of analogues in an attemptt o exploit adamantane's role in bioactivity.W ep repared as eries of adamantane carbohydrazones [22] and showedt hat these derivatives are very potent trypanocidals.…”

“…The 4-(adamant-1-yl)phenyl)hydrazides, 1a-d,were prepared by previously described methods, [22] using as startingm aterials ethyl 4-(adamant-1-yl)benzoate (2), [18] ethyl 4-(adamant-1-yl)phenyla cetate (4), [18] ethyl 4-(adamant-1-yl)phenylpropionate (6), [18] and ethyl 4-(adamant-1-yl)phenoxyacetate (8), [23] as shown in Scheme 1.…”