Spirofused Tetrahydroisoquinoline-Oxindole Hybrids (Spiroquindolones) as Potential Multitarget Antimalarial Agents: Preliminary Hit Optimization and Efficacy Evaluation in Mice.

Previous studies suggest that 3',5'-dihydro-2'H-spiro[indoline-3,1'-isoquinolin]-2-ones (DSIIQs [spiroquindolones]) are multitarget antiplasmodial agents that combine the actions of spiroindolone and naphthylisoquinoline antimalarial agents. In this study, 12 analogues of compound (±)-5 (moxiquindole), the prototypical spiroquindolone, were synthesized and tested for antiplasmodial activity. Compound (±)-11 (a mixture of compounds 11a and 11b), the most potent analogue, displayed low-nanomolar activity against P. falciparum chloroquine-sensitive 3D7 strain (50% inhibitory concentration [IC50] for 3D7 = 21 ± 02 nM) and was active against all major erythrocytic stages of the parasite life cycle (ring, trophozoite, and schizont); it also inhibited hemoglobin metabolism and caused extensive vacuolation in parasites. In drug-resistant parasites, compound (±)-11 exhibited potent activity (IC50 for Dd2 = 58.34 ± 2.04 nM) against the P. falciparum multidrug-resistant Dd2 strain, and both compounds (±)-5 and (±)-11 displayed significant cross-resistance against the P. falciparum ATP4 mutant parasite Dd2 SJ733 but not against the Dd2 KAE609 strain. In mice, both compounds (±)-5 and (±)-11 displayed dose-dependent reduction of parasitemia with suppressive 50% effective dose (ED50) values of 0.44 and 0.11 mg/kg of body weight, respectively. The compounds were also found to be curative in vivo and are thus worthy of further investigation.

Costus afer Protects Cardio-, Hepato-, and Reno-Antioxidant Status in Streptozotocin-Intoxicated Wistar Rats.

Medicinal plants are efficient modulators of oxidative stress associated with diabetes mellitus. This study evaluated the cardio-, reno-, and hepato-antioxidant status of hydroethanolic extract of Costus afer on streptozotocin-intoxicated diabetic rats. Experimental animals were daily administered with hydroethanolic extract of C. afer by oral intubation for eight weeks (60 days), after which the levels of catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), and lipid peroxidation marker (MDA) were evaluated in the heart, liver, and kidney homogenates. Plasma biochemical parameters such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total protein, creatinine, and urea were determined. Meanwhile, parts of the heart, kidneys, and liver were histopathologically examined. Streptozotocin administration induced toxicity in the cardiac, hepatic, and renal tissues by stimulating significant increases (p<0.05) in the levels of CAT and SOD, GSH, and MDA. Similarly, significant increases (P<0.05) in the levels of ALT, AST, urea, and total protein were observed in streptozotocin treated rats, whereas decreases were observed in the levels of ALP, LDH, and creatinine. Following the treatments with C. afer hydroethanolic extract prevented the effect of streptozotocin by maintaining the tissue antioxidant status (CAT, SOD, GSH, and MDA) and the plasma biochemical parameters (AST, ALT, ALP, LDH, creatinine, and urea) towards the normal ranges. The histopathological examination revealed hepatovascular congestion and leucocyte infiltration as well as renovascular congestion, glomerulosclerosis, and tubular clarification in the untreated diabetic control and their absence in the group of animals treated with a high dose of C. afer extract. The findings of the present investigation suggest that C. afer possesses antioxidant activities capable of regulating drug induced tissue damage.

Evaluation of the antidiabetic and antioxidant properties of Morinda lucida stem bark extract in streptozotocin intoxicated rats.

The present research evaluated the antidiabetic and antioxidant properties of M. lucida stem bark (50 and 500mg/kg) and glibenclamide (25mg/kg, standard drug) in acute (Oral glucose tolerance test) and sub-acute (Streptozotocin 60mg/kg, i.p. diabetic model) administration. A group of healthy rats constituted the normal control. The sub-acute experiment lasted 28 days during which water, food intake and weight gain were measured and biochemical parameters analyzed in both plasma and erythrocytes at the end of the experiment. The chemical substances present in M. lucida bark extract were determined. In the Oral glucose tolerance test, the reduction of blood glucose level was statistically significant for both M. lucida extracts and glibenclamide. However, in the diabetic rats acute administration of 500mg/kg extract had better blood sugar lowering effect than glibenclamide, which was better than 50mg/kg extract. Streptozotocin diabetic animal model was characterized by a decrease in weight gain, erythrocyte SOD and CAT activities and an increase in water and food consumption, lipid peroxidation, cholesterol, triglycerides, plasma glucose, creatinine and urea concentrations, and transaminases activities. M. lucida extract and glibenclamide significantly prevented the alteration of these parameters, thus indicating a corrective effect on diabetes and its complications. This study justifies the traditional claim and provides a rationale for the use of M. lucida to treat diabetes. Its antioxidant properties may serve to curb oxidative stress and hence prevent the diabetic complications related to oxidative stress. Chemical substances, which may be accountable for the antidiabetic and antioxidant properties of M. lucida were detected in the aqueous extract of M. lucida bark.

Costus afer Possesses Carbohydrate Hydrolyzing Enzymes Inhibitory Activity and Antioxidant Capacity In Vitro.

Diabetes mellitus is a metabolic disorder of glucose metabolism which correlates with postprandial hyperglycemia and oxidative stress. Control of blood glucose level is imperative in the management of diabetes. The present study tested the hypothesis that Costus afer, an antihyperglycemic medicinal plant, possesses inhibitory activity against carbohydrate hydrolyzing enzymes. Hexane, ethyl acetate, methanol, and water extracts were prepared from the leaf, stem, and rhizome of C. afer and subjected to phytochemical screening, assayed for α-amylase and α-glucosidase inhibitory activities and antioxidant capacity (determined by total phenolic and total flavonoids contents, ferric reducing antioxidant power (FRAP), and DPPH radical scavenging activity). All extracts inhibited α-amylase and α-glucosidase activities. Ethyl acetate rhizome and methanol leaf extracts exhibited the best inhibitory activity against α-amylase and α-glucosidase (IC50: 0.10 and 5.99 mg/mL), respectively. Kinetic analysis revealed two modes of enzyme inhibition (competitive and mixed). All extracts showed antioxidant capacity, with hexane extracts exhibiting the best activity. DPPH assay revealed that methanol leaf, rhizome, and ethyl acetate stem extracts (IC50 < 5 mg/mL) were the best antioxidants. The presence of bioactive compounds such as flavonoids, alkaloids, phenols, and tannins may account for the antioxidant capacity and carbohydrate hydrolyzing enzyme inhibitory activity of C. afer.