Koneni V. Sashidhara

The marine sponge metabolite mycothiazole: A novel prototype mitochondrial complex I inhibitor

A natural product chemistry-based approach was applied to discover small-molecule inhibitors of hypoxia-inducible factor-1 (HIF-1). A Petrosaspongia mycofijiensis marine sponge extract yielded mycothiazole (1), a solid tumor selective compound with no known mechanism for its cell line-dependent cytotoxic activity. Compound 1 inhibited hypoxic HIF-1 signaling in tumor cells (IC(50) 1nM) that correlated with the suppression of hypoxia-stimulated tumor angiogenesis in vitro. However, 1 exhibited pronounced neurotoxicity in vitro. Mechanistic studies revealed that 1 selectively suppresses mitochondrial respiration at complex I (NADH-ubiquinone oxidoreductase). Unlike rotenone, MPP(+), annonaceous acetogenins, piericidin A, and other complex I inhibitors, mycothiazole is a mixed polyketide/peptide-derived compound with a central thiazole moiety. The exquisite potency and structural novelty of 1 suggest that it may serve as a valuable molecular probe for mitochondrial biology and HIF-mediated hypoxic signaling.

Synthesis and in vitro evaluation of novel coumarin-chalcone hybrids as potential anticancer agents.

A series of coumarin-chalcone hybrids have been synthesized and evaluated for their in vitro cytotoxicity against a panel of four human cancer cell lines and normal fibroblasts (NIH3T3). Among 21 compounds screened, three compounds (23, 25 and 26) showed IC(50) range from 3.59 to 8.12 μM. The most promising compound 26 showed around 30-fold more selectivity towards C33A (cervical carcinoma) cells over normal fibroblast NIH3T3 cells with an IC(50) value of 3.59 μM.

Synthesis and antihyperlipidemic activity of novel coumarin bisindole derivatives.

A series of novel coumarin bisindole heterocycles were synthesized following an uncommon method and evaluated for their antihyperlipidemic activity in hyperlipidemic hamster model. Among 12 compounds tested, the compound 5e showed potent antihyperlipidemic activity and was found to decrease the plasma triglyceride levels (TG) by 55%, total cholesterol (TC) by 20%, accompanied by an increase in HDL-C/TC ratio by 42% in hyperlipidemic rats to a greater degree than some of the reference statins.

Discovery of coumarin-dihydropyridine hybrids as bone anabolic agents.

The concept of molecular hybridization led us to discover a novel series of coumarin-dihydropyridine hybrids that have potent osteoblastic bone formation in vitro and that prevent ovariectomy-induced bone loss in vivo. In this context, among all the compounds screened for alkaline phosphatase activity, four compounds 10, 14, 18, and 22 showed significant activity at picomolar concentrations. A series of other in vitro data strongly suggested compound 18 as the most promising bone anabolic agent, which was further evaluated for in vivo studies. From these studies compound 18 proved to be useful, which at low oral dose of 1 (mg/kg)/day body weight increased bone mass density and volume, expression of osteogenic genes (RUNX2, BMP-2, and ColI), bone formation rate (BFR), and mineral apposition rate (MAR), improved the trabecular microarchitecture, and decreased bone turn over markers in an ovariectomized rodent model for postmenopausal osteoporosis.

Discovery and synthesis of novel 3-phenylcoumarin derivatives as antidepressant agents

A series of 3-phenylcoumarins were synthesized and screened for potential antidepressant activity by tail suspension test (TST) in mice. Three compounds (6, 7 and 13) exhibited impressive antidepressant activity, measured in terms of percentage decrease in immobility duration (% DID). In addition, the active antidepressant compounds were subsequently studied at their most effective dose and activity of these compounds were confirmed in forced swimming test (FST) animal model, in which the compounds at a low dose of 0.5 mg/kg significantly decreased the immobility time and exhibited greater efficacy than the reference standards fluoxetine and imipramine. The potent compounds did not show any neurotoxicity in the rotarod test and the preliminary results are promising enough to warrant further studies around this scaffold.

Rare dipeptide and urea derivatives from roots of Moringa oleifera as potential anti-inflammatory and antinociceptive agents.

In the course of our studies on the isolation of bioactive compounds from the roots of Moringa oleifera, a traditional herb in southeast Asia, rare aurantiamide acetate 4 and 1,3-dibenzyl urea 5 have been isolated and characterized. And also, this is the first report of isolation from this genus. Isolated compound inhibited the production of TNF-alpha and IL-2; further compound 5 showed significant analgesic activities in a dose dependant manner. These findings may help in understanding the mechanism of action of this traditional plant leading to control of activated mast cells on inflammatory conditions like arthritis, for which the crude extract has been used.

Indole-Based Fibrates as Potential Hypolipidemic and Antiobesity Agents

Hypolipidemic and antiobesity effects of the newly synthesized indole-based fibrates were evaluated in Triton WR-1339 and high fat diet (HFD)-induced hyperlipidemic rats. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton model), in which compounds 3f and 3l showed significant antidyslipidemic activity. Furthermore, these compounds 3f and 3l were found to induce significant weight loss in the visceral fat mass of HFD-fed hyperlipidemic rats without affecting the normal feeding behavior. Histological examination of the liver of rats supplemented with 3f and 3l revealed a significant decrease in steatosis when compared to the effect of the standard drug fenofibrate. Additional effects such as an increase in lecithin cholesterol acyl-transferase (LCAT) enzyme level and increased receptor mediated catabolism of I(131)-low density lipoproteins (LDL) confirm and reinforce the efficacy of both of these compounds as a new class of dual-acting hypolipidemic and antiobesity agents.

Synthesis and anti-inflammatory activity of novel biscoumarin–chalcone hybrids☆

A series of synthesized novel biscoumarin-chalcone hybrids were evaluated for their anti-inflammatory and antioxidant activity. The tested compounds significantly inhibit the carrageenin induced paw oedema in albino rats and also exhibit important scavenging activities. These compounds thus constitute an interesting template for the design of new therapeutic tools against inflammation.

Discovery of coumarin–monastrol hybrid as potential antibreast tumor-specific agent

Development of new, targeted antibreast cancer drug which can treat both the hormone receptor (positive and negative) breast cancers is a very challenging task. The concept of molecular hybridization led us to discover a novel class of coumarin-monastrol hybrid, as a novel breast cancer agent which selectively induce apoptosis in both primary and metastatic breast cancer cell lines.

16α‐Hydroxycleroda‐3,13 (14)Z‐dien‐15,16‐olide from Polyalthia longifolia: a safe and orally active antileishmanial agent

Background and purpose:  New antileishmanials from natural products are urgently needed due to the emergence of drug resistance complicated by severe cytotoxic effects. 16α‐Hydroxycleroda‐3,13 (14)Z‐dien‐15,16‐olide (Compound 1) from Polyalthia longifolia was found to be a potential antileishmanial and non‐cytotoxic, as evidenced by long‐term survival (>6 months) of treated animals. This prompted us to determine its target and, using molecular modelling, identify the interactions responsible for its specific antileishmanial activity.