Assessment of Leishmanicidal and Trypanocidal Activities of Aliphatic Diamine Derivatives. (10th August 2013)

• Record Type: Journal Article
• Authors: Yamanaka, Celina N.; Giordani, Raquel B.; Rezende, Celso O.; Eger, Iriane; Kessler, Rafael L.; Tonini, Maiko L.; de, Milene H.; Araújo, Debora P.; Zuanazzi, Jose A.; de, Mauro V.; Steindel, Mario
• Is Part Of: Chemical biology & drug design. Volume 82:Number 6(2013:Dec.)
• Page Start: 697
• Page End: 704
• Publication Date: 2013-08-10
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12191
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" id="cbdd12191-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Leishmanicidal and trypanocidal activity of seventeen lipophilic diamines was evaluated <italic>in vitro</italic> against <italic>Leishmania braziliensis</italic>, <italic> L. chagasi</italic>, and <italic>Trypanosoma cruzi</italic>. Twelve compounds presented anti‐<italic>Leishmania</italic> and six showed anti‐<italic>T. cruzi</italic> amastigote activity. Compound <bold>14</bold> (<italic>N</italic>‐tetradecyl‐1, 4‐butanediamine) was the most active against both <italic>L. braziliensis</italic> (IC<sub>50</sub> = 2.6 μ<sc>m</sc>) and <italic>L. chagasi</italic> (IC<sub>50</sub> = 3.0 μ<sc>m</sc>) which showed a selectivity index (SI) >100. <italic>N</italic>‐decyl‐1, 6‐hexanediamine (compound <bold>9</bold>) presented an IC<sub>50</sub> = 1.6 μ<sc>m</sc> and SI >187 and was over six times more potent than the reference drug benznidazole against <italic>T. cruzi</italic>. Treatment of infected or uninfected macrophages with compounds <bold>9</bold> and <bold>14</bold> did not induce significant TNFα and NO production. Four compounds (<bold>15</bold>, <bold> 16</bold>, <bold> 22</bold>, and <bold>23</bold>) inhibited 78.9%, 77.7%, 83.7%, and 70.1% of rTRLb activity, respectively, and compound <bold>23</bold> inhibited 73.3% of rTRTc activity at 100 μ<sc>m</sc>. A concentration‐dependent effect on mitochondrial membrane depolarization was observed in <italic>T. cruzi</italic> epimastigotes treated with compound <bold>9</bold>, suggesting this mechanism may be involved in the trypanocidal effect. On the contrary, in <italic>L. braziliensis</italic> promastigotes treated with compound <bold>14</bold>, no mitochondrial depolarization was observed. Our results demonstrate that <italic>N</italic>‐decyl‐1, 6‐hexanediamine and <italic>N</italic>‐tetradecyl‐1, 4‐butanediamine are promising molecules for the development of novel leading compounds against <italic>T. cruzi</italic> and <italic>Leishmania</italic> spp., particularly given a possible alternative mechanism of action.</p> </abstract>