Antiplasmodial activities of gold(I) complexes involving functionalized N-heterocyclic carbenes.

A series of twenty five molecules, including imidazolium salts functionalized by N-, O- or S-containing groups and their corresponding cationic, neutral or anionic gold(I) complexes were evaluated on Plasmodium falciparum in vitro and then on Vero cells to determine their selectivity. Among them, eight new compounds were synthesized and fully characterized by spectroscopic methods. The X-ray structures of three gold(I) complexes are presented. Except one complex (18), all the cationic gold(I) complexes show potent antiplasmodial activity with IC50 in the micro- and submicromolar range, correlated with their lipophilicity. Structure-activity relationships enable to evidence a lead-complex (21) displaying a good activity (IC50=210nM) close to the value obtained with chloroquine (IC50=514nM) and a weak cytotoxicity.

Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure.

Plasmodium falciparum resistance to artemisinin derivatives in Southeast Asia threatens global malaria control strategies. Whether delayed parasite clearance, which exposes larger parasite numbers to artemisinins for longer times, selects higher-grade resistance remains unexplored. We investigated whether long-lasting artemisinin pressure selects a novel multidrug-tolerance profile. Although 50% inhibitory concentrations for 10 antimalarial drugs tested were unchanged, drug-tolerant parasites showed higher recrudescence rates for endoperoxides, quinolones, and an antifolate, including partner drugs of recommended combination therapies, but remained susceptible to atovaquone. Moreover, the age range of intraerythrocytic stages able to resist artemisinin was extended to older ring forms and trophozoites. Multidrug tolerance results from drug-induced quiescence, which enables parasites to survive exposure to unrelated antimalarial drugs that inhibit a variety of metabolic pathways. This novel resistance pattern should be urgently monitored in the field because this pattern is not detected by current assays and represents a major threat to antimalarial drug policy.

Acute Oral Toxicity Evaluation of Andrographolide Self-Nanoemulsifying Drug Delivery System (SNEDDS) Formulation.

CONTEXT: Andrographolide (AND) is an active compound of well-known medicinal plant Andrographis paniculata. It has been widely published for various activities. AND is difficult to develop into dosage form due to its poor solubility and bioavailability. This problem could be solved by using self-nanoemulsifying drug delivery system (SNEDDS) for its formulation. However, the increase of bioavailability might result in potential toxicity as a large amount of drug is absorbed. AIMS: The aim of this study is to evaluate the acute potential toxicity using Organization for Economic Cooperation and Development (OECD) test: 401 methods. SUBJECTS AND METHODS: The OECD 401 method employs groups of animals treated by a single dose or repeated dose (<24 h) of the drug with three variances of doses. In this study, thirty male Wistar rats were divided into five groups which consisted two groups of control and three groups of AND SNEDDS formulation (500, 700, and 900 mg/kg body weight [BW], respectively). Intensive observation of toxicity symptom was performed during the first 30 minutes followed by periodic observation for 14 days. Posttermination, histopathological examination of the liver and kidney was conducted to confirm the toxicity symptoms. To determine the level of toxicity, the lethal dose 50 (LD50) value was calculated at the end of the study. RESULTS: The result showed that all groups presented similar toxicological symptoms such as salivation, lethargy, and cornea reflex. However, based on histopathological examination, there were abnormalities, but still in an early stage. The toxicological symptom that emerged seems related to the SNEDDS formulation with lipophilic properties. Furthermore, the value of LD50 was 832.6 mg/kg BW (po). CONCLUSIONS: The AND SNEDDS formulation was slightly toxic in male Wistar rats po.

Cytotoxic activity of flavonoid from local plant Eriocaulon cinereum R.B against MCF-7 breast cancer cells.

Eriocaulon cinereum R. Br is used as traditional medicine by the local community in Bangka Belitung Island, Indonesia. The plant is processed as an infusion for fever, boosts the immune system, and treats tumor cells. However, scientific research on this species is still limited. The aims of this study were to determine the cytotoxic of E. cinereum against MCF-7 cells. The results suggested that one of the compounds has a good cytotoxic activity. Therefore, it is quite promising in the effort of cancer drug discovery. The active compound has a flavonoid, which plays a role in several anticancer mechanisms. This study provided scientific evidence regarding the utilization of E. cinereum by the local community for cancer therapy. The plant can be further developed as an alternative agent to treat cancer or as cancer adjuvant therapy.

Evaluation of antiplasmodial and antileishmanial activities of herbal medicine Pseudelephantopus spiralis (Less.) Cronquist and isolated hirsutinolide-type sesquiterpenoids.

ETHNOPHARMACOLOGICAL RELEVANCE: Pseudelephantopus spiralis (Less.) Cronquist is distributed in the Caribbean, Mesoamerica and Latin America. Preparations of the plant are traditionally used in Latin America for the treatment of various diseases including fever, malaria, and spleen or liver inflammations. MATERIALS AND METHODS: Aerial parts of P. spiralis were extracted with either ethanol or distilled water. Seven hirsutinolide-type sesquiterpenoids were isolated: 8-acetyl-13-ethoxypiptocarphol (1), diacetylpiptocarphol (2), piptocarphins A (3), F (4) and D (5), (1S(*),4R(*),8S(*),10R(*))-1,4-epoxy-13-ethoxy-1,8,10-trihydroxygermacra-5E,7(11)-dien-6,12-olide (6), and piptocarphol (7). Extracts and isolated compounds (2, 3, 5-7) were screened for their in vitro antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum strain FcM29-Cameroon and antileishmanial activity against three stages of Leishmania infantum. Their cytotoxicities were also evaluated against healthy VERO cell lines and J774A.1 macrophages, the host cells of the Leishmania parasites in humans. RESULTS: Aqueous extracts showed a greater inhibitory effect than alcoholic extracts, with IC50 on P. falciparum of 3.0µg/mL versus 21.1µg/mL, and on L. infantum of 13.4µg/mL versus >50µg/mL. Both extracts were found to be cytotoxic to VERO cells (CC50<3µg/mL). Sesquiterpene lactones 2 and 3 showed the best activity against both parasites but failed in selectivity. Carbon 8 hydroxylated hirsutinolides 5-7 presented the particularity of exhibiting two conformers observed in solution during extensive NMR analyses in CD3OD and UHPLC-MS. The presence of a hydroxyl function at C-8 decreased the activity of 5-7 on the two parasites and also on VERO cells. CONCLUSION: The antiplasmodial activity displayed by the aqueous extract explains the traditional use of P. spiralis in the treatment of malaria. This activity seems to be attributable to the presence of sesquiterpene lactones 2 and 3, the most active against P. falciparum. Aqueous extract and compounds 2, 3 and 6 were also active against L. infantum but lacked in selectivity due to their cytotoxicity towards macrophages. Exploring the safety and antiplasmodial efficacy of this traditional remedy will require further toxicological and in vivo studies in the light of the cytotoxicity towards healthy cell lines displayed by the aqueous extract and compounds 2 and 3.

Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates.

The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ≤0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites.