Abstract
Sixteen 1,4-diaryl-1,2,3-triazole compounds derived from the natural products veraguensin, grandisin and machilin G were synthesized, with yields of 78-92%. Biological activity tests against Leishmania amazonensis promastigotes showed that three of these compounds were the most active, with maximum inhibitory concentration (IC50) values of 1.1, 3.71 and 7.23 µM. One compound was highly active against Leishmania infantum, with an IC50 value of 5.2 µM, and one derivative showed an IC50 value of 28.6 µM against Trypanosoma cruzi trypomastigotes. Regarding structure-activity relationship (SAR), hybrid 1,2,3-triazolic compounds containing a methylenedioxy group, showed the best antileishmanial and antitrypanosomal activities.
Highlights
Leishmaniases are a group of infectious diseases with diverse clinical manifestations, ranging from cutaneous to visceral forms
This study addressed the synthesis of sixteen 1,4-diaryl-1,2,3-triazole derivatives with substitution patterns based on neolignans 1-3, intending to clarify whether substitution of tetrahydrofuran by 1,2,3-triazole core, could providing compounds with improved antitrypanosomatid activity
The synthesis of starting materials began by preparing aryl bromides 21b-c via a bromination reaction of 20b-c in the presence of N-bromosuccinimide (NBS), p-TsOH, CH2Cl2 and SiO2.28 Subsequently, a cross-coupling Sonogashira reaction between bromobenzenes 21a-c and 2-methyl-3-butyn-2-ol in the presence of PdCl2(PPh3)2/CuI, Et3N provided the acetylene alcohols 22a-c with 75-85% yields, after 24 h reaction time.[29,30]
Summary
Leishmaniases are a group of infectious diseases with diverse clinical manifestations, ranging from cutaneous to visceral forms. Studies on the antitrypanosomal activity of compounds 1-3 found maximum inhibitory concentration (IC50) values of 2.3, 3.7 and 2.2 μM, respectively.[21,22,23] Veraguensin 1 and machilin G 3 showed potential antileishmanial activity, with an IC50 value of 18 μg mL-1 (48.8 and 50.54 μM, respectively) against L. donovani.[16] The synthesis of derivatives could improve these biological effects.
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