Peganine hydrochloride dihydrate an orally active antileishmanial agent

Protozoic infections caused by genus Leishmania pose an enormous public health threat in developing countries, compounded by the toxicity and resistance to current therapies. Under the aegis of our ongoing program on drug discovery and development on antileishmanial agents from plants, we carried out bioassay guided fractionation on Peganum harmala seeds which resulted in the isolation of 1 as an antileishmanial agent. 2D-NMR spectral data and single crystal X-ray crystallography data indicated 1 as peganine hydrochloride in dihydrated form. The compound 1 exhibited in-vitro activity against both extracellular promastigotes as well as intracellular amastigotes residing within murine macrophages in Leishmania donovani. Furthermore, 1 also exhibited in-vivo activity, 79.6 (±8.07)% against established VL in hamsters at a dose of 100 mg/kg b.wt.     

Identification of the benzodiazepines as a new class of antileishmanial agent

The continual increase in drug resistance; the lack of new chemotherapeutic agents; the toxicity of existing agents and the increasing morbidity with HIV co-infection mean the search for new antileishmanial agents has never been more urgent. We have identified the benzodiazepines as a structural class for antileishmanial hit optimisation, and demonstrated that their in vitro activity is comparable with the clinically used drug, sodium stibogluconate, and that the compounds are not toxic to macrophages.     

Synthesis and biological evaluation of polyhydroxylated oxindole derivatives as potential antileishmanial agent

The devastating appearance of numerous drug-unresponsive strains of Leishmania donovani and severe toxic side effects of conventional antileishmanial therapy necessitates the search for novel leads, to treat visceral leishmaniasis efficiently. The current study deals with the synthesis and biological evaluation of a unique C-5 functionalized oxindole based polyphenol to ascertain its activities against L. donovani infection, in vitro. The polyhydroxylated oxindole derivative (1) was generated by coupling styrene derivatives with 5-bromo bis-arylidene oxindole using Heck coupling reaction. The synthesized molecule 1 was tested for its antileishmanial activity using both promastigote and amastigote stages of L. donovani. Molecule 1 showed promising anti-promastigote and anti-amastigote activities with IC₅₀ values 15?µM and 1?µM, respectively, with no cytotoxicity towards host splenocytes. The results revealed that this compound induced parasite death by promoting oxidative stress, thereby triggering apoptosis.     

Oleanolic acid (OA) as an antileishmanial agent: Biological evaluation and in silico mechanistic insights

Although a worldwide health problem, leishmaniasis is considered a highly neglected disease, lacking efficient and low toxic treatment. The efforts for new drug development are based on alternatives such as new uses for well-known drugs, in silico and synthetic studies and naturally derived compounds. Oleanolic acid (OA) is a pentacyclic triterpenoid widely distributed throughout the Plantae kingdom that displays several pharmacological activities. OA showed potent leishmancidal effects in different Leishmania species, both against promastigotes (IC_{50 L. braziliensis} 30.47 ± 6.35 μM; IC_{50 L. amazonensis} 40.46 ± 14.21 μM; IC_{50 L. infantum} 65.93 ± 15.12 μM) and amastigotes (IC_{50 L. braziliensis} 68.75 ± 16.55 μM; IC_{50 L. amazonensis} 38.45 ± 12.05 μM; IC_{50 L. infantum} 64.08 ± 23.52 μM), with low cytotoxicity against mouse peritoneal macrophages (CC₅₀ 235.80 ± 36.95 μM). Moreover, in silico studies performed to evaluate OA molecular properties and to elucidate the possible mechanism of action over the Leishmania enzyme sterol 14α-demethylase (CYP51) suggested that OA interacts efficiently with CYP51 and could inhibit the ergosterol synthesis pathway. Collectively, these data indicate that OA is a good candidate as leading compound for the development of a new leishmaniasis treatment.     

Potential of an antagonistic bacterium isolate obtained fromLentinus lepideus basidiospores as a biocontrol agent

TheBurkholderia sp. isolate 87-11 obtained from basidiospores ofLentinus lepideus was antagonistic against severalPythium andRhizoctonia isolates. The bacterium was tested against soilborne diseases of five plants caused byP. aphanidermatum andR. solani by soil and seed application, and its potential as a biocontrol agent is discussed.     

Azaterphenyl diamidines as antileishmanial agents

Eighteen diamidino azaterphenyls and analogues were evaluated as anti-leishmanials; nine of the compounds gave IC50 values less than 1 microM, five exhibited values less than 0.40 microM, and two gave values less than 0.10 microM in a Leishmania donovani axenic amastigote assay. The activity of the diamidines strongly depends on the ring N-atom location relative to the amidine groups and correlates with DNA affinity. Transmission electron microscopy studies showed a dramatic dilation of the mitochondrion and evidence of disintegration of the kinetoplast of the amastigotes.     

Tumor delivery of liposomal doxorubicin prepared with poly-L-glutamic acid as a drug-trapping agent

Context: Poly-l-glutamic acid (PGA) is an anionic polymer with a large number of carboxyl groups that can interact electrostatically with cationic drugs such as doxorubicin (DOX).

Objective: For stable encapsulation of DOX into liposomes, we prepared triethylamine (TEA)-PGA-liposomes using PGA as an internal trapping agent.

Methods: We prepared TEA-PGA-liposomes by remote loading of DOX with a TEA gradient into preformed liposomes prepared with 1, 2, or 4?mg/mL PGA (molecular weights 4800, 9800, and 20 500), and evaluated their biodistribution and antitumor effects on Lewis lung carcinoma (LLC) tumor-bearing mice.

Results: TEA-PGA-liposomes using the higher the molecular weight or concentration of PGA showed a slower release of DOX from the liposomes. TEA-PGA-liposomes prepared with a high concentration of PGA could enhance DOX accumulation in tumors and prolonged DOX circulation in the serum, indicating that DOX may be retained stably in the liposomal interior by interaction with PGA. Furthermore, injection of TEA-PGA-liposomes prepared with 4?mg/mL of PGA₉₈₀₀ or 2?mg/mL PGA₂₀₅₀₀ strongly inhibited tumor growth in LLC tumor-bearing mice.

Conclusions: PGA may be a potential trapping agent for liposomal DOX for tumor drug delivery.     

Reserpine as an uncoupling agent

1. Reserpine, like the uncoupling agent, 2,4-dinitrophenol prevents oxidative phosphorylation but stimulates the rate at which oxygen is reduced.

2. Both reserpine and 2,4-dinitrophenol fail to stimulate oxygen uptake by isolated mitochondria in the presence of arginine.

3. Both 2,4-dinitrophenol and reserpine induce proton permeability in the mitochondrial membrane so that H⁺ is absorbed from the suspending medium.

4. When the reaction system contains reserpine, accumulation of Ca²⁺ by mitochondria is inhibited.

5. Reserpine decreases both ADP:O and P:O ratios which strongly suggest that reserpine is an uncoupling agent.     

Thalidomide as an anti-cancer agent

Thalidomide is a glutamic acid derivative initially introduced as a sedative hypnotic nearly forty years ago. It was withdrawn following numerous reports linking it to a characteristic pattern of congenital abnormalities in babies born to mothers who used the drug for morning sickness. It has gradually been re-introduced into clinical practice over the past two decades, albeit under strict regulation, since it was found to be useful in the management of erythema nodosum leprosum and HIV wasting syndrome. Recognition of its anti-angiogenic effect led to its evaluation in the treatment of various malignancies, where angiogenesis has been shown to play an important role. Numerous clinical trials done over the past four years have confirmed the significant anti-myeloma activity of this drug. It has also shown promise in preliminary trials in the treatment of a variety of different malignant diseases. The mechanisms of its antineoplastic effects continue to be the focus of ongoing research. It has become clear that even though its anti angiogenic effects play a significant role in the anti-tumor activity, there are other properties of this drug which are responsible as well. It also possesses anti-TNF alpha activity, which has led to its evaluation in several inflammatory states. In this concise review, we briefly describe the historical background and pharmacological aspects of this drug. We have concisely reviewed the current knowledge regarding mechanisms of its anti-neoplastic activity and the results of various clinical trials in oncology.     

Delivery in vivo of 14-deoxy-11-oxoandrographolide, an antileishmanial agent, by different drug carriers

An antileishmanial compound, 14-deoxy-11-oxo-andrographolide, a derivative of andrographlide, isolated from the Indian medicinal plant Andrographis paniculata was evaluated for efficacy in free form and in different vesicular delivery modes on hamster model of Leishmaniasis. The subcutaneous injection of free drug reduced the spleen parasite load by 39%, whereas for drug incorporated in liposomes, niosomes and microspheres, reductions in the parasite load were 78%, 91% and 59%, respectively. Moreover, the drug in various delivery modes, particularly in liposomal and niosomal forms, showed no apparent immediate toxicity. Although an inverse linear relationship between the size of carriers and per cent efficacy in reduction of spleen parasite load was established, involvement of other factors such as drug release profiles or rates remains an open question. Because of greater efficacy and lesser toxicity, liposomal, niosomal and possibly microsphere-incorporated 14-deoxy-11-oxo-andrographolide might have clinical application to combat visceral Leishmaniasis.     

Evaluation of a diospyrin derivative as antileishmanial agent and potential modulator of ornithine decarboxylase of Leishmania donovani

World health organization has called for academic research and development of new chemotherapeutic strategies to overcome the emerging resistance and side effects exhibited by the drugs currently used against leishmaniasis. Diospyrin, a bis-naphthoquinone isolated from Diospyros montana Roxb., and its semi-synthetic derivatives, were reported for inhibitory activity against protozoan parasites including Leishmania. Presently, we have investigated the antileishmanial effect of a di-epoxide derivative of diospyrin (D17), both in vitro and in vivo. Further, the safety profile of D17 was established by testing its toxicity against normal macrophage cells (IC₅₀ ∼ 20.7 μM), and also against normal BALB/c mice in vivo. The compound showed enhanced activity (IC₅₀ ∼ 7.2 μM) as compared to diospyrin (IC₅₀ ∼ 12.6 μM) against Leishmania donovani promastigotes. Again, D17 was tested on L. donovani BHU1216 isolated from a sodium stibogluconate-unresponsive patient, and exhibited selective inhibition of the intracellular amastigotes (IC₅₀ ∼ 0.18 μM). Also, treatment of infected BALB/c mice with D17 at 2 mg/kg/day reduced the hepatic parasite load by about 38%. Subsequently, computational docking studies were undertaken on selected enzymes of trypanothione metabolism, viz. trypanothione reductase (TryR) and ornithine decarboxylase (ODC), followed by the enzyme kinetics, where D17 demonstrated non-competitive inhibition of the L. donovani ODC, but could not inhibit TryR.     

gem-Dithioacetylated indole derivatives as novel antileishmanial agents

In this communication we report a serendipitously discovered hybrid molecule 1, combining fragment of 3 (an in vivo active antileishmanial molecule) with H₂S donor moiety (known for bimodal behavior of cytoprotection and apoptosis), as antileishmanial agent. Compound 1 suppresses 99.82% parasitemia of L. donovani infected macrophages at 12.5 μg/ml without even deforming them (CC₅₀ > 100 μg/ml). This compound appears cytotoxic for intracellular amastigotes while cytoprotective to host macrophages. The concept can be utilized to develop high therapeutic index NCE (New Chemical Entities) for other macrophage mediated diseases like tuberculosis and cancer.     

Phytoestrogen genistein as an anti-staphylococcal agent

The soybean-derived isoflavone genistein has been shown to exert beneficial effects on many disorders, including cancer and cardiovascular diseases. The effects of genistein on mammalian cells are mediated by its abilities to inhibit topoisomerase II and protein tyrosine kinase. In order to examine the potential antibacterial activities of genistein, we incubated the bacteria with various concentrations of this compound for different periods of time and assessed the viable counts. Exposure to genistein exhibited an inhibitory effect on all staphylococcal strains tested, including methicillin-resistant strains. Furthermore, the growth of Streptococcus pasteurianus, Bacillus cereus, and Helicobacter pylori was clearly inhibited by genistein, whereas Escherichia coli growth was not suppressed. Daidzein, which is structurally similar to genistein, but deficient in topoisomerase II inhibitory activity, also inhibited the growth of Staphylococcus aureus, albeit with lower potency than genistein. Our results indicate that genistein exerts potent antibacterial properties in vitro, which are possibly mediated by the stabilization of the covalent topoisomerase II-DNA cleavage complex.     

Drosophila cecropin as an antifungal agent

The effects of Drosophila and Hyalophora cecropins were tested against different fungi, both insect pathogens and fungi from the normal environment of Drosophila. The fungi were generally found to be as susceptible to the cecropins as most bacteria, the only exception being the insect pathogen Beauveria bassiana which is completely resistant. This is also the only fungus tested which is virulent to Drosophila, giving 100% lethality within 5 days after injection. Lethal concentrations of cecropins against other fungi tested ranged between 0.4 and 4 microM. Andropin is less fungicidal than the cecropins, and Drosophila cecropin A is somewhat more potent than cecropin B. Even dense cultures of Saccharomyces cerevisiae can be cleared by micromolar concentrations of cecropin, whereas Geotrichum candidum is unaffected by cecropin when tested in a dense culture.     

Methylene blue as an antimalarial agent

Methylene blue has intrinsic antimalarial activity and it can act as a chloroquine sensitizer. In addition, methylene blue must be considered for preventing methemoglobinemia, a serious complication of malarial anemia. As an antiparasitic agent, methylene blue is pleiotropic: it interferes with hemoglobin and heme metabolism in digestive organelles, and it is a selective inhibitor of Plasmodium falciparum glutathione reductase. The latter effect results in glutathione depletion which sensitizes the parasite for chloroquine action. At the Centre de Recherche en Santé de Nouna in Burkina Faso, we study the combination of chloroquine with methylene blue (BlueCQ) as a possible medication for malaria in endemic regions. A pilot study with glucose-6-phosphate dehydrogenase-sufficient adult patients has been conducted recently.