Discovery of Safe and Orally Effective 4-Aminoquinaldine Analogues as Apoptotic Inducers with Activity against Experimental Visceral Leishmaniasis

Palit, Partha; Hazra, Abhijit; Maity, Arindam; Vijayan, Ramachandran; Manoharan, Prabu; Banerjee, Sukdeb; Mondal, Nirup B.; Ghoshal, Nanda; Ali, Nahid

doi:10.1128/aac.00700-11

Cited by 18 publications

(13 citation statements)

References 55 publications

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“…The reduced formazan, which is a measure of cell viability, was dissolved in dimethyl sulfoxide. The absorbance at 550 nm was measured in a spectrophotometer (Hitachi Electronics, Japan) (24).…”

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confidence: 99%

Cationic Liposomal Sodium Stibogluconate (SSG), a Potent Therapeutic Tool for Treatment of Infection by SSG-Sensitive and -Resistant Leishmania donovani

Sinha

Roychoudhury

Palit

et al. 2015

Antimicrob Agents Chemother

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Pentavalent antimonials have been the first-line treatment for leishmaniasis for decades. However, the development of resistance to sodium stibogluconate (SSG) has limited its use, especially for treating visceral leishmaniasis (VL). The present work aims to optimize a cationic liposomal formulation of SSG for the treatment of both SSG-sensitive (AG83) and SSG-resistant (GE1F8R and CK1R) Leishmania donovani infections. Parasite killing was determined by the 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide (MTT) assay and microscopic counting of Giemsa-stained macrophages. Macrophage uptake studies were carried out by confocal microscopic imaging. Parasite-liposome interactions were visualized through transmission electron microscopy. Toxicity tests were performed using assay kits. Organ parasite burdens were determined by microscopic counting and limiting dilution assays. Cytokines were measured by enzyme-linked immunosorbent assays (ELISAs) and flow cytometry. Although all cationic liposomes studied demonstrated leishmanicidal activity, phosphatidylcholine (PC)-dimethyldioctadecylammonium bromide (DDAB) vesicles were most effective, followed by PC-stearylamine (SA) liposomes. Since entrapment of SSG in PC-DDAB liposomes demonstrated enhanced ultrastructural alterations in promastigotes, PC-DDAB-SSG vesicles were further investigated in vitro and in vivo. PC-DDAB-SSG could effectively alleviate SSG-sensitive and SSG-resistant L. donovani infections in the liver, spleen, and bone marrow of BALB/c mice at a dose of SSG (3 mg/kg body weight) not reported previously. The parasiticidal activity of these vesicles was attributed to better interactions with the parasite membranes, resulting in direct killing, and generation of a strong host-protective environment, necessitating a very low dose of SSG for effective cures. V isceral leishmaniasis (VL), caused by the protozoan parasiteLeishmania donovani, results in 0.2 to 0.4 million cases reported annually and poses a threat to about 200 million people worldwide. With the advent of the human immunodeficiency viruses, VL has surged as an opportunistic infection among AIDS patients (1). Pentavalent antimonial drugs are the first-line drugs against all forms of leishmaniasis, although their use for the treatment of VL has been discontinued in India due to the emergence of resistance. Extended treatment regimens, parenteral administration, and toxic side effects limit patient compliance with treatment. Frequent therapeutic failures due to resistance to the antimonial drug sodium stibogluconate (SSG) necessitate the use of second-line drugs such as amphotericin B (AMB), which are more toxic. Alternate therapies for VL have resulted in the development of several lipid-and liposome-based formulations of conventional drugs, with enhanced efficacies and reduced toxicities (2-7). The advantages of the use of liposomes as drug delivery vehicles for treating macrophage-resident parasites such as Leishmania involve their ease of preparation, low toxicity, and biodegradabilit...

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Cationic Liposomal Sodium Stibogluconate (SSG), a Potent Therapeutic Tool for Treatment of Infection by SSG-Sensitive and -Resistant Leishmania donovani

Sinha

Roychoudhury

Palit

et al. 2015

Antimicrob Agents Chemother

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“…Compound 1 resulted in a nearly twofold increase in ROS levels with respect to control culture at 3 h (MFI: control 232.24, treatment 481. [21] GSH is also important for protecting the parasites from ROS and other toxic compounds. Hydrogen peroxide, as a positive control, increased ROS levels in promastigotes relative to compound 1 (3.5-fold; Figure 6 a).…”

Section: Induction Of Oxidative Stress and Decreased Intracellular Gsmentioning

confidence: 99%

Synthesis and Biological Evaluation of Ferrocenylquinoline as a Potential Antileishmanial Agent

et al. 2015

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The emergence of resistance against antileishmanial drugs in current use necessitates the search for new classes of antileishmanial compounds. Herein we report the design, synthesis, and evaluation of a novel ferrocenylquinoline for activity against Leishmania donovani. 7-Chloro-N-[2-(1H-5-ferrocenyl-1,2,3-triazol-1-yl)ethyl]quinolin-4-amine (1) was generated by coupling an iron(II) ethynylferrocene species with 4-(2-ethylazido)amino-7-chloroquinoline using click chemistry. The synthesized compound 1 was tested for its antileishmanial activity using both promastigote and amastigote stages of L. donovani. Compound 1 showed promising anti-promastigote activity, with an IC50 value of 15.26 μM and no cytotoxicity toward host splenocytes. From the battery of tests conducted in this study, it appears that this compound induces parasite death by promoting oxidative stress and depolarizing the mitochondrial membrane potential, thereby triggering apoptosis. These results suggest that ferrocenylquinoline 1 is a suitable lead for the development of new antileishmanial drugs.

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“…Both the compounds did not cause any changes in haematological or cardiac functions in BALB/c mice and were not hepato or nephrotoxic. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of dihydrofolate reductase and elicitation of the apoptotic cascade 79 .…”

Section: Investigational Drugsmentioning

confidence: 99%

Investigational drugs for visceral leishmaniasis

Sundar

Chakravarty

2014

Expert Opinion on Investigational Drugs

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Introduction The armamentarium of antileishmanials is small. It is further being threatened by development of resistance and decreasing sensitivity to the available drugs. Development of newer drugs are sorely needed. Areas covered Literature search on investigational drugs for visceral leishmaniasis (VL) was done on PubMed. Those candidates with at least in vitro and in vivo activity against leishmania species causing VL were reviewed. Among the investigational drugs the nitroimidazole compound fexinidazole is the one of the few drugs which has reached phase II trials. Although the (S)-PA-824 is in phase II trials for the treatment of tuberculosis its R enantiomer has shown good antileishmanial activity. Development of sitamaquin, which has completed phase II studies has been stopped for VL due to its low efficacy. Many novel delivery system and oral formulations of Amphotericin B which are cheap and less toxic are in investigational stages, and will go a long way in improving the treatment of VL. Expert opinion Very few new drugs have reached the clinical stage in the treatment of this neglected tropical disease. Thus, there is an urgent need for support from public private partnerships to ensure that drug candidates are promptly taken forward into development.

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Discovery of Safe and Orally Effective 4-Aminoquinaldine Analogues as Apoptotic Inducers with Activity against Experimental Visceral Leishmaniasis

Cited by 18 publications

References 55 publications

Cationic Liposomal Sodium Stibogluconate (SSG), a Potent Therapeutic Tool for Treatment of Infection by SSG-Sensitive and -Resistant Leishmania donovani

Cationic Liposomal Sodium Stibogluconate (SSG), a Potent Therapeutic Tool for Treatment of Infection by SSG-Sensitive and -Resistant Leishmania donovani

Synthesis and Biological Evaluation of Ferrocenylquinoline as a Potential Antileishmanial Agent

Investigational drugs for visceral leishmaniasis

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