SAR:s for the Antiparasitic Plant Metabolite Pulchrol. 1. The Benzyl Alcohol Functionality

Abstract

<jats:p>Pulchrol (1) is a natural benzochromene isolated from the roots of Bourreria pulchra, shown to possess potent antiparasitic activity towards both Leishmania and Trypanozoma species. As it is not understood which molecular features of 1 are important for the antiparasitic activity, several analogues were synthesized and assayed. The ultimate goal is to understand the structure–activity relationships (SAR:s) and create a QSAR model that can be used for the development of clinically useful antiparasitic agents. In this study, we have synthesized 25 2-methoxy-6,6-dimethyl-6H-benzo[c]chromen analogues of 1 and its co-metabolite pulchral (5a), by semi-synthetic procedures starting from the natural product pulchrol (1) itself. All 27 compounds, including the two natural products 1 and 5a, were subsequently assayed in vitro for antiparasitic activity against Trypanozoma cruzi, Leishmania brasiliensis and Leishmania amazoniensis. In addition, the cytotoxicity in RAW cells was assayed, and a selectivity index (SI) for each compound and each parasite was calculated. Several compounds are more potent or equi-potent compared with the positive controls Benznidazole (Trypanozoma) and Miltefosine (Leishmania). The compounds with the highest potencies as well as SI-values are esters of 1 with various carboxylic acids.</jats:p>

SARs for the Antiparasitic Plant Metabolite Pulchrol. Part 2: B- and C-Ring Substituents

“…The new alkyl groups were introduced by a double addition step to the ester group in 4 using the corresponding organolithium reagents. For the cyclization of 6a and 6b to 8f and 8g , an excess in hydroiodic acid was used, to avoid the formation of cannabidiol type byproducts as a result of elimination [ 28 ]. Nevertheless, the byproducts 9a and 9b appeared together with 8f , and 9c and 9d with 8g .…”

“…Pulchrol also showed moderate leishmanicidal activity against L. braziliensis and L. amazonesis promastigotes, with IC 50 values of 59.2 μM and 77.7 μM, respectively. The effects that modifications of the benzylic alcohol functionality of 1 have on the antiparasitic activity were studied previously [ 28 ], and especially esters of the alcohol increased the potency significantly. In this study, we evaluate how modifications on ring B and C affect the antiparasitic activity against T. cruzi , L. braziliensis and L. amazonensis .…”

“…Pulchrol ( 1 ) was found to possess antiparasitic activity against Leishmania braziliensis , L. amazonensis , L. mexicana and Trypanosoma cruzi [ 22 , 25 ]. A synthetic route was developed in 2014 [ 26 , 27 ], and recently we reported the effects that transformations of its A-ring benzyl alcohol functionality have against T. cruzi epimastigotes, L. amazonensis promastigotes and L. braziliensis promastigotes, as well as their cytotoxicity towards mammalian cells (assayed in RAW cells) [ 28 ]. We are now interested to expand the previous study [ 28 ] with compounds having various substituents in the B- and C-rings.…”

“…A synthetic route was developed in 2014 [ 26 , 27 ], and recently we reported the effects that transformations of its A-ring benzyl alcohol functionality have against T. cruzi epimastigotes, L. amazonensis promastigotes and L. braziliensis promastigotes, as well as their cytotoxicity towards mammalian cells (assayed in RAW cells) [ 28 ]. We are now interested to expand the previous study [ 28 ] with compounds having various substituents in the B- and C-rings. Our aim is to use the synthetic routes and some of the intermediates used for the synthesis of pulchrol ( 1 ), to obtain new derivatives.…”

SARs for the Antiparasitic Plant Metabolite Pulchrol. 3. Combinations of New Substituents in A/B-Rings and A/C-Rings

“…The potential shown by pulchrol ( 1a ) as an antiparasitic agent against T. cruzi and the Leishmania species led to the development of a synthetic route [ 42 , 43 ] that yields sufficient amounts of pulchrol to perform additional biological assays. This could also be adapted for the preparation of a series of analogues with individual transformations of the benzyl alcohol moiety in the A-ring [ 44 ], variations at positions 1, 2 and 3 in the C-ring, and modifications at the only available position in the B-ring (C-6) [ 45 ]. In this investigation, we prepared analogues with combinations of different functionalities in the A-, B-, and C-rings (see Figure 2 ), inspired by some of the SARs observed in the previous studies [ 44 , 45 ].…”