EF24, a schistosomicidal curcumin analog: Insights from its synthesis and phenotypic, biochemical and cytotoxic activities.

Praziquantel (PZQ) is the only drug available for community-based control programs which aim to reduce the prevalence and morbidity associated with schistosomiasis. Here, we synthesized and evaluated the schistosomicidal, biochemical and cytotoxic activities of EF24, a synthetic curcumin analog, against different isolates of Schistosoma mansoni. EF24 elicited marked phenotypic alterations at 10 µM against schistosomula and 42-day-old adult worms of the Naval Medical Research Institute (NMRI) isolate. EF24 had 50% effective concentration (EC50) values of <10 µM against the Luis Evangelista (LE), Sergipe (SE), Belo Horizonte (BH) and Belo Horizonte less sensitive to PZQ (BH < PZQ) isolates of adult S. mansoni; however, the respective sensitivities of these isolates differed. Changes in the parasite included, vacuolization of the tegument and focal lysis of the interstitial tissue and muscle layers. Against 28-day-old juvenile worms (LE isolate), EF24 was about three times more potent than PZQ. After 6 h at 12.5 µM, EF24 increased reactive oxygen species (ROS) and the activity of the antioxidant enzyme, glutathione-S-transferase (GST), by 32 and 19% in female and male adult worms, respectively. By contrast, after 6 h at 12.5 µM glutathione reductase (GR) activity decreased by 43 and 30%, and glutathione peroxidase (GPx) activity decreased by 67 and 44% in females and males, respectively. EF24 was less cytotoxic to mammalian host cells than to S. mansoni, with selectivity indexes (SIs) of 1.8-3.4 and 2.7-7.5 for juvenile and adult worms, respectively. Given the current evidence for the in vitro schistosomicidal effect of EF24, the structure-activity relationship of additional analogs to identify new candidates for schistosomiasis treatment is warranted.

Monoketonic Curcuminoid-Lidocaine Co-Deliver Using Thermosensitive Organogels: From Drug Synthesis to Epidermis Structural Studies.

Organogels (ORGs) are remarkable matrices due to their versatile chemical composition and straightforward preparation. This study proposes the development of ORGs as dual drug-carrier systems, considering the application of synthetic monoketonic curcuminoid (m-CUR) and lidocaine (LDC) to treat topical inflammatory lesions. The monoketone curcuminoid (m-CUR) was synthesized by using an innovative method via a NbCl5-acid catalysis. ORGs were prepared by associating an aqueous phase composed of Pluronic F127 and LDC hydrochloride with an organic phase comprising isopropyl myristate (IPM), soy lecithin (LEC), and the synthesized m-CUR. Physicochemical characterization was performed to evaluate the influence of the organic phase on the ORGs supramolecular organization, permeation profiles, cytotoxicity, and epidermis structural characteristics. The physico-chemical properties of the ORGs were shown to be strongly dependent on the oil phase constitution. Results revealed that the incorporation of LEC and m-CUR shifted the sol-gel transition temperature, and that the addition of LDC enhanced the rheological G'/G″ ratio to higher values compared to original ORGs. Consequently, highly structured gels lead to gradual and controlled LDC permeation profiles from the ORG formulations. Porcine ear skin epidermis was treated with ORGs and evaluated by infrared spectroscopy (FTIR), where the stratum corneum lipids were shown to transition from a hexagonal to a liquid crystal phase. Quantitative optical coherence tomography (OCT) analysis revealed that LEC and m-CUR additives modify skin structuring. Data from this study pointed ORGs as promising formulations for skin-delivery.

Licochalcone a Exhibits Leishmanicidal Activity in vitro and in Experimental Model of Leishmania (Leishmania) Infantum.

The efficacy of Licochalcone A (LicoA) and its two analogs were reported against Leishmania (Leishmania) amazonensis and Leishmania (Leishmania) infantum in vitro, and in experimental model of L. (L.) infantum in vitro. Initially, LicoA and its analogs were screened against promastigote forms of L. (L.) amazonensis. LicoA was the most active compound, with IC50 values of 20.26 and 3.88 µM at 24 and 48 h, respectively. Against amastigote forms, the IC50 value of LicoA was 36.84 µM at 48 h. In the next step, the effectivity of LicoA was evaluated in vitro against promastigote and amastigote forms of L. (L.) infantum. Results demonstrated that LicoA exhibited leishmanicidal activity in vitro against promastigote forms with IC50 values of 41.10 and 12.47 µM at 24 and 48 h, respectively; against amastigote forms the IC50 value was 29.58 µM at 48 h. Assessment of cytotoxicity demonstrated that LicoA exhibited moderate mammalian cytotoxicity against peritoneal murine macrophages; the CC50 value was 123.21 µM at 48 h and showed about 30% of hemolytic activity at concentration of 400 µM. L. (L.) infantum-infected hamsters and treated with LicoA at 50 mg/kg for eight consecutive days was able to significantly reduce the parasite burden in both liver and spleen in 43.67 and 39.81%, respectively, when compared with negative control group. These findings suggest that chalcone-type flavonoids can be a promising class of natural products to be considered in the search of new, safe, and effective compounds capable to treat canine visceral leishmaniosis (CVL).

The binding of synthetic triiodo l-thyronine analogs to human transthyretin: molecular basis of cooperative and non-cooperative ligand recognition.

Transthyretin (TTR) is a tetrameric ß-sheet-rich transporter protein directly involved in human amyloid diseases. Several classes of small molecules can bind to TTR delaying its amyloid fibril formation, thus being promising drug candidates to treat TTR amyloidoses. In the present study, we characterized the interactions of the synthetic triiodo L-thyronine analogs and thyroid hormone nuclear receptor TRß-selective agonists GC-1 and GC-24 with the wild type and V30M variant of human transthyretin (TTR). To achieve this aim, we conducted in vitro TTR acid-mediated aggregation and isothermal titration calorimetry experiments and determined the TTR:GC-1 and TTR:GC-24 crystal structures. Our data indicate that both GC-1 and GC-24 bind to TTR in a non-cooperative manner and are good inhibitors of TTR aggregation, with dissociation constants for both hormone binding sites (HBS) in the low micromolar range. Analysis of the crystal structures of TTRwt:GC-1(24) complexes and their comparison with the TTRwt X-ray structure bound to its natural ligand thyroxine (T4) suggests, at the molecular level, the basis for the cooperative process displayed by T4 and the non-cooperative process provoked by both GC-1 and GC-24 during binding to TTR.

A short and efficient synthesis of crocetin-dimethylester and crocetindial.

In this paper we describe an efficient six-step synthesis of crocetin-dimethylester that could be further reduced to a "four-step" synthesis through the use of in situ procedures. The simplicity of the whole process, the ready availability of starting materials, and the high overall yield render this strategy a very attractive synthesis of this very important compound, which is the key intermediate for the synthesis of several carotenoids and other polyene natural products.