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

Abstract

Neglected tropical diseases affect most of the underprivileged populations in tropical countries. Among these are chagas and leishmaniasis, present mainly in South and Central America, Africa and East Asia. Current treatments are long and have severe adverse effects, therefore there is a strong need to develop alternatives. In this study, we base our research on the plant metabolite pulchrol, a natural benzochromene which has been shown to possess antiparasitic activity against Trypanosoma and Leishmania species. In a recent study, we investigated how changes in the benzyl alcohol functionality affected the antiparasitic activity, but the importance of B- and C-ring substituents is not understood. Fifteen derivatives of pulchrol with different substituents in positions 1, 2, 3, and 6 while leaving the A-ring intact, were therefore prepared by total synthesis, assayed, and compared with pulchrol and positive controls. The generated series and parental molecule were tested in vitro for antiparasitic activity against Trypanosoma cruzi, Leishmania braziliensis, and L. amazonensis, and cytotoxicity using RAW cells. Substantial differences in the activity of the compounds synthesized were observed, of which some were more potent towards Trypanosoma cruzi than the positive control benznidazole. A general tendency is that alkyl substituents improve the potency, especially when positioned on C-2.

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

“…The synthetic routes used to prepare the analogues were partially based on the already reported procedure that was used to prepare pulchrol from biaryl intermediates [ 42 , 43 ]. The molecules in the 1 -series (see Figure 2 ) were previously reported [ 44 , 45 ], and were used as the starting material to prepare the compounds from the 2 -, 3 -, 4 - and 5 -series, containing a 1′-aldehyde, 1′-methyl ketone, 3-methylbutanoic acid ester, and 9-methyl functionalities, respectively (see Figure 2 ). Compound 5f (cannabinol) and its analogue 5e were obtained through iodine-mediated deconstructive annulation in a one-pot synthesis, using citral and resorcinol analogues as the starting material [ 46 ].…”

“…Pulchrol ( 1a ) has been reported to be moderately active against L. braziliensis and L. amazonensis promastigotes (IC 50 59.2 μM and IC 50 77.7 μM, respectively), while it has been shown to possess potent toxicity towards T. cruzi epimastigotes (IC 50 18.5 μM), comparable to that of the drug benznidazole (19.2 μM) that currently is used as treatment for Chagas disease. Meanwhile, pulchral ( 2a ) has been shown to be active against all of the three parasites ( T. cruzi , IC 50 24.2 μM; L. braziliensis , IC 50 24.2 μM; L. amazonensis , IC 50 29.8 μM) [ 44 , 45 ].…”

“…In previous investigations, we studied the effect that individual transformations in the A-, B-, and C-rings have on the activity towards T. cruzi , L. braziliensis and L. amazonensis [ 44 , 45 ]. Initially, we reported the effect of the modifications at position 1′ in the A-ring, and concluded preliminarily that the benzyl alcohol functionality was important for pulchrol’s activity towards all of the three parasites, possibly acting as a hydrogen bond acceptor.…”

“…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 ].…”

“…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 ]. Cannabinol ( 5f ) and its 3-methyl analogue 5e (see Figure 2 ) were also prepared and assayed.…”