A new Heck reaction modification using ketone Mannich bases as enone precursors: Parallel synthesis of anti-leishmanial chalcones

Reichwald, Christina; Shimony, Orly; Sacerdoti‐Sierra, Nina; Jaffe, Charles L.; Kunick, Conrad

doi:10.1016/j.bmcl.2008.01.112

Cited by 19 publications

(5 citation statements)

References 24 publications

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“…Some Paullone derivatives were reported as either inefficient within THP1 macrophages and/or too toxic for the host cell [42]. A second class of compounds (chalcone derivatives; compounds c10 , c13-16 ) was identified that did not induce any noticeable phenotype in our assay (Figure 3), although they have been previously identified as active against L. donovani axenic amastigotes in the micromolar range [43]. Finally, Acivicin ( c49 ), Aphidicolin ( c51 ) and Phenyltoxamine ( c52 ) did not exhibit any activity on intramacrophagic amastigotes (Figure 3), even though these molecules were described previously as potent growth inhibitors for L. major promastigotes by Sharlow and coworkers [10].…”

Section: Resultsmentioning

confidence: 83%

High Content Analysis of Primary Macrophages Hosting Proliferating Leishmania Amastigotes: Application to Anti-leishmanial Drug Discovery

et al. 2013

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Background/ObjectivesHuman leishmaniases are parasitic diseases causing severe morbidity and mortality. No vaccine is available and numerous factors limit the use of current therapies. There is thus an urgent need for innovative initiatives to identify new chemotypes displaying selective activity against intracellular Leishmania amastigotes that develop and proliferate inside macrophages, thereby causing the pathology of leishmaniasis.Methodology/Principal FindingsWe have developed a biologically sound High Content Analysis assay, based on the use of homogeneous populations of primary mouse macrophages hosting Leishmania amazonensis amastigotes. In contrast to classical promastigote-based screens, our assay more closely mimics the environment where intracellular amastigotes are growing within acidic parasitophorous vacuoles of their host cells. This multi-parametric assay provides quantitative data that accurately monitors the parasitic load of amastigotes-hosting macrophage cultures for the discovery of leishmanicidal compounds, but also their potential toxic effect on host macrophages. We validated our approach by using a small set of compounds of leishmanicidal drugs and recently published chemical entities. Based on their intramacrophagic leishmanicidal activity and their toxicity against host cells, compounds were classified as irrelevant or relevant for entering the next step in the drug discovery pipeline.Conclusions/SignificanceOur assay represents a new screening platform that overcomes several limitations in anti-leishmanial drug discovery. First, the ability to detect toxicity on primary macrophages allows for discovery of compounds able to cross the membranes of macrophage, vacuole and amastigote, thereby accelerating the hit to lead development process for compounds selectively targeting intracellular parasites. Second, our assay allows discovery of anti-leishmanials that interfere with biological functions of the macrophage required for parasite development and growth, such as organelle trafficking/acidification or production of microbicidal effectors. These data thus validate a novel phenotypic screening assay using virulent Leishmania amastigotes growing inside primary macrophage to identify new chemical entities with bona fide drug potential.

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Section: Resultsmentioning

confidence: 83%

High Content Analysis of Primary Macrophages Hosting Proliferating Leishmania Amastigotes: Application to Anti-leishmanial Drug Discovery

et al. 2013

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“…Amongst a set of chalcones, compounds 89a and 89b inhibited axenic L. donovani amastigotes at 15 µM with more than 90%. However, they caused a definite cell killing at 1 µM on human macrophage THP-1 cells [107]. Sulfonamide and methoxy moieties were evaluated as promising adding-groups to chalcones by synthesis of sulfonamide 4-methoxychalcone derivatives (90a -h).…”

Section: Antiparasitic Activitymentioning

confidence: 99%

Trends in Utilization of the Pharmacological Potential of Chalcones

Batovska

Todorova²

2010

CCP

296

206

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Chalcones (1,3-diaryl-2-propen-1-ones) are open chain flavonoids that are widely biosynthesized in plants. They are important for the pigmentation of flowers and, hence, act as attractants to the pollinators. As flavonoids, chalcones also play an important role in defense against pathogens and insects. A longstanding scientific research has shown that chalcones also display other interesting biological properties such as antioxidant, cytotoxic, anticancer, antimicrobial, antiprotozoal, antiulcer, antihistaminic and anti-inflammatory activities. Some lead compounds with various pharmacological properties have been developed based on the chalcone skeleton. Clinical trials have shown that these compounds reached reasonable plasma concentrations and did not cause toxicity. For these reasons, chalcones became an object of continued interest in both academia and industry. Nowadays, several chalcones are used for treatment of viral disorders, cardiovascular diseases, parasitic infections, pain, gastritis, and stomach cancer, as well as like food additives and cosmetic formulation ingredients. However, much of the pharmacological potential of chalcones is still not utilized. The purpose of this review is to describe the recent efforts of scientists in pharmacological screening of natural and synthetic chalcones, studying the mechanisms of chalcone action and relevant structure-activity relationships. Put together, these activities aimed at synthesis of pharmacologically active chalcones and their analogs.

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“…ment. Representative examples of bioactive nicotinoyl derivatives are shown in Figure 2, which includes the N-phenylnicotinoyl derivative 16 as human sirtuin-2-selective inhibitor, [6] 17 as sodium channel blocker, [7] 18 as soluble epoxideh ydrolase inhibitor, [8] 19 as HDAC1/HDAC2 inhibitor, [9] 20 as anti-leishma-nial agent, [10] and 21 as aquaporin 4i nhibitor. [11] The N-biphenyl-4-ylnicotinamide analogue of 21,w hich may be considered as at emplate of the compounds investigatedh erein, proved to be active against ap anel of bioassays, such as HIV-1 RNase Hi nhibition,M KP-3, HePTP,H sp70, ER stress-induced cell death andV HR1 in vitro high throughput screening.…”

Section: Introductionmentioning

confidence: 99%

Investigating Structural Requirements for the Antiproliferative Activity of Biphenyl Nicotinamides

et al. 2017

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A number of trimethoxybenzoic acid anilides, previously studied as permeability glycoprotein (P-gp) modulators, were screened with the aim of identifying new anticancer agents. One of these compounds, which showed antiproliferative activity against resistant MCF-7 cell line, was selected as the hit structure. Replacement of the trimethoxybenzoyl moiety with a nicotinoyl group, in order to overcome solubility issues, led to a new series of N-biphenyl nicotinoyl anilides, among which a nitro derivative, N-(3',5'-difluoro-3-nitro-[1,1'-biphenyl]-4-yl)nicotinamide (3), displayed antiproliferative activity against MCF-7 and MDA-MB-231 cells in the nanomolar range. The search for a bioisostere of the nitro group led to nitrile analogue N-(3-cyano-4'-fluoro-[1,1'-biphenyl]-4-yl)nicotinamide (36), which shows a strong increase in activity against MCF-7 and MDA-MB-231 cells. Compound 36 induced a dose-dependent accumulation of G - and M-phase MCF-7 cell populations, and a decrease in S-phase cells. Relative to vinblastine, a well-known potent antimitotic agent, compound 36 also induced G -phase arrest at low doses (20-40 nm), but did not inhibit in vitro tubulin polymerization.

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A new Heck reaction modification using ketone Mannich bases as enone precursors: Parallel synthesis of anti-leishmanial chalcones

Cited by 19 publications

References 24 publications

High Content Analysis of Primary Macrophages Hosting Proliferating Leishmania Amastigotes: Application to Anti-leishmanial Drug Discovery

High Content Analysis of Primary Macrophages Hosting Proliferating Leishmania Amastigotes: Application to Anti-leishmanial Drug Discovery

Trends in Utilization of the Pharmacological Potential of Chalcones

Investigating Structural Requirements for the Antiproliferative Activity of Biphenyl Nicotinamides

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