Immunization with a Trypanosoma cruzi cyclophilin-19 deletion mutant protects against acute Chagas disease in mice.

Human infection with the protozoan parasite Trypanosoma cruzi causes Chagas disease for which there are no prophylactic vaccines. Cyclophilin 19 is a secreted cis-trans peptidyl isomerase expressed in all life stages of Trypanosoma cruzi. This protein in the insect stage leads to the inactivation of insect anti-parasitic peptides and parasite transformation whereas in the intracellular amastigotes it participates in generating ROS promoting the growth of parasites.

Repurposing of existing therapeutics to combat drug-resistant malaria.

In the era of drug repurposing, speedy discovery of new therapeutic options for the drug-resistant malaria is the best available tactic to reduce the financial load and time in the drug discovery process. Six anticancer drugs, three immunomodulators and four antibiotics were selected for the repositioning against experimental malaria owing to their mode of action and published literature. The efficacy of existing therapeutics was evaluated against chloroquine-resistant in vitro and in vivo strains of Plasmodium falciparum and P.

Synthesis, SAR and biological studies of sugar amino acid-based almiramide analogues: N-methylation leads the way.

Leishmaniasis, caused by the protozoan parasites of the genus Leishmania, is one of the most neglected diseases endemic in many continents posing enormous global health threats and therefore the discovery of new antileishmanial compounds is of utmost urgency. The antileishmanial activities of a library of sugar amino acid-based linear lipopeptide analogues were examined with the aim to identify potential drug candidates to treat visceral leishmaniasis. It was found that among the synthesized analogues, most of the permethylated compounds exhibited more activity in in vitro studies against intra-macrophagic amastigotes than the non-methylated analogues.

Identification of a diverse indole-2-carboxamides as a potent antileishmanial chemotypes.

A novel series of highly diverse indole-2-carboxamides was synthesized utilizing the isocyanide based multicomponent reaction (IMCR)-post modification approach and were identified as potential antileishmanial chemotype. Among the synthesized 18 analogues, 12 analogues exhibited better antileishmanial activity against intracellular amastigotes form of Leishmania donovani (IC50 values of 0.6-7.

Cross reactive molecules of human lymphatic filaria Brugia malayi inhibit Leishmania donovani infection in hamsters.

Coinfections are common in natural populations and the outcome of their interactions depends on the immune responses of the host elicited by the parasites. Earlier we showed that immunization with BmAFII (Sephadex G-200 eluted) fraction of human lymphatic filaria Brugia malayi inhibited progression of Leishmania donovani infection in golden hamsters. In the present study we identified cross reactive molecules of B.

Aminothiazoles: Hit to lead development to identify antileishmanial agents.

As part of Drugs for Neglected Diseases initiative's lead optimization program for the development of new chemical entities to treat visceral leishmaniasis (VL), a series of aminothiazoles were synthesized and screened for in vitro efficacy, solubility and microsomal stability. The primary aim of identifying a lead structure with sub-micromolar activity was achieved. Out of 43 compounds synthesized, 16 compounds showed in vitro activity at less than 1 μM against VL.

Leptin augments protective immune responses in murine macrophages and enhances potential of miltefosine against experimental visceral leishmaniasis.

Adverse side effects and drug resistance issues are the two most important drawbacks which influence the widespread use of existing antileishmanial drugs. Use of immune stimulating agent with standard antileishmanial might be helpful to minimize the toxic effect of drug, shorten the dose regimen and delay the emergence of resistance. In the present study, we explored the in vitro immunomodulatory potential of an immunomodulator, leptin with lower concentration of standard drug, miltefosine.

Chemotherapy of leishmaniasis part XIII: design and synthesis of novel heteroretinoid-bisbenzylidine ketone hybrids as antileishmanial agents.

Some novel heteroretinoid-bisbenzylidine ketone hybrids have been synthesized and evaluated for their in vitro antileishmanial activity against intramacrophagic amastigotes of Leishmania donovani. Among all the nine synthetic compounds, five compounds (7c, 7d and 7f-h) have shown significant (less than 7μM) activity against intramacrophagic amastigotes. The IC50 values of these compounds were found better than the reference drugs sodium stibogluconate (SSG) and miltefosine.

Nitroimidazo-oxazole compound DNDI-VL-2098: an orally effective preclinical drug candidate for the treatment of visceral leishmaniasis.

Objectives: The objective of this study was to identify a nitroimidazo-oxazole lead molecule for the treatment of visceral leishmaniasis (VL).

Methods: A library of 72 nitroimidazo-oxazoles was evaluated in vitro for their antileishmanial activity against luciferase-transfected DD8 amastigotes of Leishmania donovani. On the basis of their in vitro potency and pharmacokinetic properties, the promising compounds were tested in acute BALB/c mouse and chronic hamster models of VL via oral administration and efficacy was evaluated by microscopic counting of amastigotes after Giemsa staining.

Discovery of triazine mimetics as potent antileishmanial agents.

The World Health Organization has classified the leishmaniasis as a major tropical disease. The discovery of new compounds for leishmaniasis is therefore a pressing concern for the anti-infective research program. We have synthesized 19 compounds of triazine dimers as novel antileishmanial agents.

Synthesis and biological evaluation of chalcones as potential antileishmanial agents.

Antileishmanial activities of thirty-five synthetic chalcones have been examined. Among them, ten compounds (4, 6, 16, 22, 23, 24, 25, 29, 35 and 37) exhibited potent in vitro activity (IC50 range from 1.70 to 8 μM) against extracellular promastigotes and intracellular amastigotes form of Leishmania donovani.

Combination of liposomal CpG oligodeoxynucleotide 2006 and miltefosine induces strong cell-mediated immunity during experimental visceral leishmaniasis.

Immuno-modulators in combination with antileishmanial drug miltefosine is a better therapeutic approach for treatment of Visceral Leishmaniasis (VL) as it not only reduces the dose of miltefosine but also shortens the treatment regimen. However, immunological mechanisms behind the perceived benefits of this combination therapy have not been investigated in detail. In the present study, we hypothesized that potential use of drugs that target the host in addition to the parasite might represent an alternative strategy for combination therapy.

Design, synthesis, ADME characterization and antileishmanial evaluation of novel substituted quinoline analogs.

In vitro ADME characterization of the lead compound 1 identified for visceral leishmaniasis was undertaken and further structural analogs were synthesized for antileishmanial screening. Compound 1 was highly permeable in intestinal PAMPA model (31 × 10(-6)cm/s) and was moderately bound to mouse and human plasma proteins (% bound 85-95%), its blood to plasma concentration ratio was less than 1, but the compound was unstable in blood. Compound 1 was found to have no CYP450 liability with CYP2C9, 2C19, 2D6 and 3A4.

Synthesis, structure-activity relationships, and biological studies of chromenochalcones as potential antileishmanial agents.

Antileishmanial activities of a library of synthetic chalcone analogues have been examined. Among them, five compounds (11, 14, 16, 17, 22, and 24) exhibited better activity than the marketed drug miltefosine in in vitro studies against the intracellular amastigotes form of Leishmania donovani. Three promising compounds, 16, 17, and 22, were tested in a L.

Triazino indole-quinoline hybrid: a novel approach to antileishmanial agents.

A novel series of 1,2,4-triazino-[5,6b]indole-3-thione covalently linked to 7-chloro-4-aminoquinoline have been synthesized and evaluated for their in vitro activity against extracellular promastigote and intracellular amastigote form of Leishmania donovani. Among all tested compounds, compounds 7a and 7b were found to be the most active with IC50 values 1.11, 0.

Design, synthesis and biological evaluation of 2-substituted quinolines as potential antileishmanial agents.

An analogous library of 2-substituted quinoline compounds was synthesized with the aim to identify a potential drug candidate to treat visceral leishmaniasis. These molecules were tested for their in vitro and in vivo biological activity against Leishmania donovani. Metabolic stability of these compounds was also improved through the introduction of halogen substituents.

Design, synthesis and biological evaluation of aryl pyrimidine derivatives as potential leishmanicidal agents.

A series of substituted aryl pyrimidine derivatives was synthesized and evaluated in vitro for their antileishmanial potential against intracellular amastigotes of Leishmania donovani using reporter gene luciferase assay. Among all, 8 compounds showed promising IC50 values ranging from 0.5 to 12.

Synthesis and biological evaluation of a novel series of aryl S,N-ketene acetals as antileishmanial agents.

A series of aryl S,N-ketene acetals 7(a-f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. All the 6 compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC50 values ranging from 1.

Discovery of a new class of natural product-inspired quinazolinone hybrid as potent antileishmanial agents.

The high potential of quinazolinone containing natural products and their derivatives in medicinal chemistry led us to discover four novel series of 53 compounds of quinazolinone based on the concept of molecular hybridization. Most of the synthesized analogues exhibited potent leishmanicidal activity against intracellular amastigotes (IC50 from 0.65 ± 0.

Chemotherapy of leishmaniasis. Part XII: design, synthesis and bioevaluation of novel triazole integrated phenyl heteroterpenoids as antileishmanial agents.

A novel series of triazole integrated phenyl heteroterpenoids have been synthesized and screened for their in vitro activity against intracellular amastigote form of Leishmania donovani. Among all tested compounds, compound 3a was found to be the most active with IC50 6.4μM and better selectivity index (SI) 18 as compared to reference drugs, miltefosine and miconazole.

Synthesis of perspicamide A and related diverse analogues: their bioevaluation as potent antileishmanial agents.

The first protocol for the synthesis of perspicamide A and related diverse analogues has been developed from economical and readily available starting materials. Furthermore, a few synthesized analogues, 24a, 24b, 24c, 24d, and 24l, exhibited potent activity against Leishmania donovani with IC(50) values ranging from 3.75 to 10.

A natural product inspired hybrid approach towards the synthesis of novel pentamidine based scaffolds as potential anti-parasitic agents.

A natural product inspired molecular hybridization approach led us to a series of novel pentamidine based pyrimidine and chalcone scaffolds. All the hybrids were evaluated for their anti-leishmanial potential. Most of the screened compounds have showed significant in vitro anti-leishmanial activity with less cytotoxicity in comparison to the standard drugs (pentamidine, sodium stibogluconate, and miltefosine).

Synthesis and evaluation of new furanyl and thiophenyl azoles as antileishmanial agents.

A series of benzyloxy furanyl and benzyloxy thiophenyl azoles were synthesized and screened for their in vitro antileishmanial activity against Leishmania donovani. Among all, 16 compounds have shown more than 90% inhibition against promastigotes at 20 μM while 11 compounds exhibited IC50 in the range of 3.04-9.