Exploring the antimalarial potential of the methoxy-thiazinoquinone scaffold: Identification of a new lead candidate

Investigating the Antiparasitic Potential of the Marine Sesquiterpene Avarone, Its Reduced Form Avarol, and the Novel Semisynthetic Thiazinoquinone Analogue Thiazoavarone

“…A chloroquine-sensitive (CQ-S) D10 and a chloroquine-resistant (CQ-R) W2 strains were used to determine the IC50 against asexual stage of parasites. The most potent compound was thiazoavarone (2) with an IC50 value in the nanomolar range, higher than those exhibited by the previously identified synthetic lead [13]. The high potency of the thiazinoquinone 2, specifically on the chloroquine-resistant strain W2 and compared with avarone (1), lacking the heterocyclic moiety, confirmed once again the high potential of the thiazinoquinone scaffold for development of new antimalarial hits.…”

“…In particular, the antiplasmodial activity was found to depend on the ability of the compound to generate a semiquinone radical species able to form a stable adduct with heme [11]. This was later supported by the design and synthesis of other sets of new thiazinoquinone derivatives, indicating that the activity was related to the ability to form a specific semiquinone radical, and to the ability of this latter to transfer the radical by and hydrogen-radical shift to the R substituent [13]. In addition, several important SARs were obtained.…”

“…In the frame of our research for new anti-parasitic chemical entities, we recently identified the thiazinoquinone scaffold as a novel chemotype active against both Plasmodium falciparum and Schistosoma mansoni [10][11][12][13][14]. We developed this scaffold by creating of a chemical library of thiazinoquinone derivatives designed on the model of aplidinones, natural products isolated from a marine invertebrate ( Figure 1).…”

“…We developed this scaffold by creating of a chemical library of thiazinoquinone derivatives designed on the model of aplidinones, natural products isolated from a marine invertebrate ( Figure 1). Many compounds exhibited in vitro antiplasmodial activities against the D10 and W2 strains of P. falciparum [11,13] with IC 50 in the low micromolar range. Through an integrated experimental (cyclic voltammetry) and theoretical approach, we demonstrated that the antiplasmodial and anticancer activity of a series of thiazinoquinone compounds was not related to their two electrons redox potential [11,12].…”

“…Pharmacological studies on synthetic and semisynthetic derivatives of avarone have been previously reported, too [23,[39][40][41]. Based on the above described extensive exploration of the thiazinoquinone scaffold as antiplasmodial and antischistosomal agent [11,13,14], we used the quinone avarone (1) as chemical starting point to obtain the semisynthetic thiazinoquinone derivative, thiazoavarone (2, Figure 2). Compound 2, as well as the natural metabolites 1 and 3, were investigated in order to evaluate their in vitro activity against: (i) asexual stages of D10 and W2 strains and stage V gametocytes of P. falciparum, (ii) egg production, larval and adult stages of S. mansoni, (iii) promastigote and amastigote stages of Leishmania infantum and Leishmania tropica.…”