Synthesis and antileishmanial activity of C7- and C12-functionalized dehydroabietylamine derivatives

Abstract

Abietane-type diterpenoids, either naturally occurring or synthetic, have shown a wide range of pharmacological actions, including antiprotozoal properties. In this study, we report on the antileishmanial evaluation of a series of (+)-dehydroabietylamine derivatives functionalized at C7 and/or C12. Thus, the activity in vitro against Leishmania infantum, Leishmania donovani, Leishmania amazonensis and Leishmania guyanensis, was studied. Most of the benzamide derivatives showed activities at low micromolar concentration against cultured promastigotes of Leishmania spp. (IC50 = 2.2-46.8 μM), without cytotoxicity on J774 macrophage cells. Compound 15, an acetamide, was found to be the most active leishmanicidal agent, though it presented some cytotoxicity on J774 cells. Among the benzamide derivatives, compounds 8 and 10, were also active against L. infantum intracellular amastigotes, being 18- and 23-fold more potent than the reference compound miltefosine, respectively. Some structure-activity relationships have been identified for the antileishmanial activity in these dehydroabietylamine derivatives.

Diterpenes as lead molecules against neglected tropical diseases

“…A clerodane diterpene in L. donovani exhibited caspase‐3/‐7‐like protease activity and genomic DNA fragmentation, induced mitochondrial dysfunction, and caused an oxidative stress‐mediated apoptotic cell death (Kathuria et al ., ), while kaurenoic acid triggered the NLRP12/IL‐1β/cNOS/NO mechanism in Leishmania amazonensis (Miranda et al ., ). A number of promising leishmicidal diterpenes have been reported (Sinha et al ., ; Sairafianpour et al ., ; Lala et al ., ; Habtemariam, ; González et al , ; Fokialakis et al ., ; Brito et al ., ; Suryawanshi et al ., ; Roy et al ., ; Dos Santos et al ., ; Mondal et al ., ; Soares et al ., ; Santos et al ., ; Mothana et al ., ; Moreira et al ., ; Mokoka et al ., ; Falodun et al ., ; Demarchi et al ., ; da Silva et al ., ; Mizuno et al ., ; Lima et al ., ; Dea‐Ayuela et al ., ). However, their mechanisms of action have not been elucidated.…”

“…In some studies, diterpenes in nanoformulations (Roy et al, 2010;Mondal et al, 2013) as well as their laboratory derivatives have been reported to exhibit promising anti-NTDs activities (Watson and Preedy, 2010;Mander and Liu, 2010). Additionally, a number of diterpenes have been reported to act against multiple strains responsible for a particular NTD (Sanchez et al, 2006;Dea-Ayuela et al, 2016;Johnson et al, 1993;Riel et al, 2002;Clarkson et al, 2003;Kalauni et al, 2006;Ojo-Amaize et al, 2007;Wangchuk et al, 2010;González et al, 2014;Namukobe et al, 2015;Liu et al, 1997;Prabu et al, 2015;Encarnación-Dimayuga et al, 2006;Rijo et al, 2010;Arai et al, 2014;Xu et al, 2014a;Xu et al, 2014b) and NTDs (Schmidt et al, 2011;Al Musayeib et al, 2014;Ramírez-Macías et al, 2012;Mothana et al, 2014;Falodun et al, 2014;Mizuno et al, 2015;Mongkolvisut and Sutthivaiyakit, 2007;Rangkaew et al, 2009;Ospina and Rodríguez, 2009;Lekphrom et al, 2010;Almutairi et al, 2014).…”

Synthesis and Biological Studies of (+)-Liquiditerpenoic Acid A (Abietopinoic Acid) and Representative Analogues: SAR Studies

“…Leishmania species (L. infantum, L. donovani, L. amazonensis and L. guyanensis), as well as for cytotoxicity against J774 macrophages following established procedures. 28 The results on extracellular forms (promastigotes)…”

Bio‐based benzoxazines based on sesamol: Synthesis and properties

“…It has been reported that furan ring structures can participate in benzoxazine crosslinking reactions and improve the crosslinking density of the system . Dehydroabietylamine is widely used in the fields of dyes, coatings, photochemical resolution, metal processing, and other fine processing . Recently, our group also successfully synthesized two fully bio‐based benzoxazines using dehydroabietylamine .…”

“…30,[34][35][36][37] Dehydroabietylamine is widely used in the fields of dyes, coatings, photochemical resolution, metal processing, and other fine processing. [38][39][40][41][42][43] Recently, our group also successfully synthesized two fully bio-based benzoxazines using dehydroabietylamine. 44 This is also the first application of dehydroabietylamine in the field of benzoxazine research.…”