Autofluorescent antimalarials by hybridization of artemisinin and coumarin: in vitro/in vivo studies and live-cell imaging.

Malaria is one of our planet's most widespread and deadliest diseases, and there is an ever-consistent need for new and improved pharmaceuticals. Natural products have been an essential source of hit and lead compounds for drug discovery. Antimalarial drug artemisinin (ART), a highly effective natural product, is an enantiopure sesquiterpene lactone and occurs in Artemisia annua L. The development of improved antimalarial drugs, which are highly potent and at the same time inherently fluorescent is particularly favorable and highly desirable since they can be used for live-cell imaging, avoiding the requirement of the drug's linkage to an external fluorescent label. Herein, we present the first antimalarial autofluorescent artemisinin-coumarin hybrids with high fluorescence quantum yields of up to 0.94 and exhibiting excellent activity in vitro against CQ-resistant and multidrug-resistant P. falciparum strains (IC50 (Dd2) down to 0.5 nM; IC50 (K1) down to 0.3 nM) compared to reference drugs CQ (IC50 (Dd2) 165.3 nM; IC50 (K1) 302.8 nM) and artemisinin (IC50 (Dd2) 11.3 nM; IC50 (K1) 5.4 nM). Furthermore, a clear correlation between in vitro potency and in vivo efficacy of antimalarial autofluorescent hybrids was demonstrated. Moreover, deliberately designed autofluorescent artemisinin-coumarin hybrids, were not only able to overcome drug resistance, they were also of high value in investigating their mode of action via time-dependent imaging resolution in living P. falciparum-infected red blood cells.

Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart.

Late sodium current (late INa) inhibition has been proposed to suppress the incidence of arrhythmias generated by pathological states or induced by drugs. However, the role of late INa in the human heart is still poorly understood. We therefore investigated the role of this conductance in arrhythmias using adult primary cardiomyocytes and tissues from donor hearts. Potentiation of late INa with ATX-II (anemonia sulcata toxin II) and E-4031 (selective blocker of the hERG channel) slowed the kinetics of action potential repolarization, impaired Ca2+ homeostasis, increased contractility, and increased the manifestation of arrhythmia markers. These effects could be reversed by late INa inhibitors, ranolazine and GS-967. We also report that atrial tissues from donor hearts affected by atrial fibrillation exhibit arrhythmia markers in the absence of drug treatment and inhibition of late INa with GS-967 leads to a significant reduction in arrhythmic behaviour. These findings reveal a critical role for the late INa in cardiac arrhythmias and suggest that inhibition of this conductance could provide an effective therapeutic strategy. Finally, this study highlights the utility of human ex-vivo heart models for advancing cardiac translational sciences.

Speeding up Viedma Deracemization through Water-catalyzed and Reactant Self-catalyzed Racemization.

Viedma deracemization is based on solution phase racemization, dissolution of racemic or scalemic conglomerates and crystal growth through autocatalytic cluster formation. With rate limiting racemization, its acceleration by appropriate catalysts may result in speeding up deracemization. A conglomerate-forming chiral compound may principally racemize directly, or via reverse of its formation reaction. For a hydrazine derivative, we investigated available racemization pathways in presence of pyrrolidine or thiourea amine as base catalysts: via Mannich or aza-Michael reaction steps and their reverse, or by enolization. Racemization by enolization was computationally found to dominate, both under water-free conditions and in presence of water, involving a multitude of different pathways. Faster racemization in presence of water resulted indeed in more rapid deracemization, when the base was pyrrolidine. Under water-free conditions, the role of water as enolization catalyst is assumed by chiral hydrazine itself - in autocatalytic racemization and in which both reactant and product are catalysts.

(Iso)Quinoline-Artemisinin Hybrids Prepared through Click Chemistry: Highly Potent Agents against Viruses.

Viral infections cause life-threatening diseases in millions of people worldwide every year and there is an urgent need for new, effective antiviral drugs. Hybridization of two chemically diverse compounds into a new bioactive effector product is a successful concept to improve the properties of a hybrid drug relative to the parent compounds. In this study, (iso)quinoline-artemisinin hybrids, obtained through copper-catalyzed azide-alkyne cycloaddition or metal-free click reactions (in organic solvents or in the presence of water), were analyzed in vitro, for the first time, for their inhibitory activity against human cytomegalovirus (HCMV), relative to their parent compounds and the reference drug ganciclovir. EC50 (HCMV) values were obtained in a range 0.22-1.20 µm, which indicated highly potent antiviral properties in the absence of cytotoxic effects on normal cells (CC50 >100 µm). The most active hybrid, 1 (EC50 =0.22 µm), is 25 times more potent than its parent compound artesunic acid (EC50 =5.41 µm) and 12 times more efficient than the standard drug ganciclovir (EC50 =2.6 µm). Interestingly, hybrid 1 also shows inhibitory activity against hepatitis B virus in vitro (EC50 (HBeAg)=2.57 µm).

Synthesis of Tamoxifen-Artemisinin and Estrogen-Artemisinin Hybrids Highly Potent Against Breast and Prostate Cancer.

In the search for new and effective treatments of breast and prostate cancer, a series of hybrid compounds based on tamoxifen, estrogens, and artemisinin were successfully synthesized and analyzed for their in vitro activities against human prostate (PC-3) and breast cancer (MCF-7) cell lines. Most of the hybrid compounds exhibit a strong anticancer activity against both cancer cell lines - for example, EC50 (PC-3) down to 1.07 µM, and EC50 (MCF-7) down to 2.08 µM - thus showing higher activities than their parent compounds 4-hydroxytamoxifen (afimoxifene, 7; EC50 =75.1 (PC-3) and 19.3 µM (MCF-7)), dihydroartemisinin (2; EC50 =263.6 (PC-3) and 49.3 µM (MCF-7)), and artesunic acid (3; EC50 =195.1 (PC-3) and 32.0 µM (MCF-7)). The most potent compounds were the estrogen-artemisinin hybrids 27 and 28 (EC50 =1.18 and 1.07 µM, respectively) against prostate cancer, and hybrid 23 (EC50 =2.08 µM) against breast cancer. These findings demonstrate the high potential of hybridization of artemisinin and estrogens to further improve their anticancer activities and to produce synergistic effects between linked pharmacophores.

Cabergoline in the Treatment of Male Orgasmic Disorder-A Retrospective Pilot Analysis.

INTRODUCTION: Male orgasmic disorder is common, with few treatment options. Cabergoline is a dopamine agonist that acts centrally to normalize serum prolactin that could improve orgasmic dysfunction. AIMS: To determine whether cabergoline increases the potential for orgasm in men with orgasmic disorder. METHODS: A retrospective chart review of men treated in a single andrology clinic for delayed orgasm or anorgasmia in a pilot study using cabergoline 0.5 mg twice weekly was performed. Duration of treatment and response were noted. Medical records were examined for other factors including history of prostatectomy and concomitant androgen supplementation. MAIN OUTCOME MEASURES: Subjective improvement in orgasmic function resulting from cabergoline treatment. RESULTS: Of 131 men treated with cabergoline for orgasmic disorder, 87 (66.4%) reported subjective improvement in orgasm and 44 (33.6%) reported no change in orgasm. Duration of therapy (P = .03) and concomitant testosterone therapy (P = .02) were associated with a significant positive response to cabergoline treatment. No differences were found between injectable and non-injectable testosterone formulations (P = .90), and neither age (P = .90) nor prior prostatectomy (P = .41) influenced the outcome of cabergoline treatment. Serum testosterone levels before (P = .26) and after (P = .81) treatment were not significantly different in responders vs non-responders. CONCLUSION: Cabergoline is a potentially effective and easy-to-administer treatment for male orgasmic disorder, the efficacy of which appears to be independent of patient age or orgasmic disorder etiology. Prospective randomized trials are needed to determine the true role of cabergoline in the treatment of this disorder.

Rapid regression of atherosclerosis with MTP inhibitor treatment.

OBJECTIVE: Regression of atherosclerosis is a vital treatment goal of atherosclerotic vascular disease. Inhibitors of the microsomal triglyceride transfer protein (MTP) have been shown to reduce apolipoprotein B (apoB)-containing lipoproteins in animals and humans effectively. Therefore, the major aim of our study is to evaluate the effect of MTP inhibition on atherosclerotic plaque regression. METHODS: LDL-receptor-deficient (LDLr(-/-)) mice were fed a Western diet for 16 weeks and then harvested for baseline (n = 8), switched to chow diet (n = 8) or chow diet containing MTP inhibitor (BMS 212122; n = 8) for 2 weeks before harvesting. RESULTS: Treatment with MTP inhibitor led to rapid reduction in plasma lipid levels, which were accompanied by a significant decrease in lipid content and monocyte-derived (CD68+) cells in atherosclerotic plaques compared to baseline and chow diet control groups. MTP inhibitor-treated mice had increased collagen content, a marker associated with increased stability in human plaques. Furthermore, plaques of these mice showed a significant decrease in tissue factor and pro-inflammatory M1 macrophage marker monocyte chemoattractant protein-1 (MCP-I) and an increase in anti-inflammatory M2 macrophage markers arginase-I and mannose receptor 1 compared to mice in the baseline group. CONCLUSION: Reversal of hyperlipidemia in atherosclerotic mice by inhibition of MTP leads to rapid and beneficial changes in the composition and inflammatory state of the plaque.