Synthesis and Insight into the Structure–Activity Relationships of Chalcones as Antimalarial Agents

Narender, Tadigoppula; Korthikunta, Venkateswarlu; Gupta, Shweta; Kancharla, Papireddy; Khaliq, Tanvir; Soni, Awakash; Srivastava, Rajeev; Srivastava, Kumkum; Puri, Sunil K.; Raju, K. Kanaka; Wahajuddin,; Sijwali, Puran Singh; Kumar, Vikash; Mohammad, Imran

doi:10.1021/jm300588j

Cited by 88 publications

(57 citation statements)

References 59 publications

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“…falciparum [5]. FP2, FP3 and their homologs in other malaria parasites prefer leucine at the P2 position in substrates and inhibitors [14–24]. Several peptidyl inhibitors of papain-like cysteine proteases, including leupeptin (acetyl-Leu–Leu–Arg-aldehyde, with P2 leucine and aldehyde warhead), block development of malaria parasites by inhibiting FP2 and FP3 [25].…”

Section: Introductionmentioning

confidence: 99%

Blocking Plasmodium falciparum Development via Dual Inhibition of Hemoglobin Degradation and the Ubiquitin Proteasome System by MG132

et al. 2013

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Among key potential drug target proteolytic systems in the malaria parasite Plasmodium falciparum are falcipains, a family of hemoglobin-degrading cysteine proteases, and the ubiquitin proteasomal system (UPS), which has fundamental importance in cellular protein turnover. Inhibition of falcipains blocks parasite development, primarily due to inhibition of hemoglobin degradation that serves as a source of amino acids for parasite growth. Falcipains prefer P2 leucine in substrates and peptides, and their peptidyl inhibitors with leucine at the P2 position show potent antimalarial activity. The peptidyl inhibitor MG132 (Z-Leu-Leu-Leu-CHO) is a widely used proteasome inhibitor, which also has P2 leucine, and has also been shown to inhibit parasite development. However, the antimalarial targets of MG132 are unclear. We investigated whether MG132 blocks malaria parasite development by inhibiting hemoglobin degradation and/or by targeting the UPS. P. falciparum was cultured with inhibitors of the UPS (MG132, epoxomicin, and lactacystin) or falcipains (E64), and parasites were assessed for morphologies, extent of hemoglobin degradation, and accumulation of ubiquitinated proteins. MG132, like E64 and unlike epoxomicin or lactacystin, blocked parasite development, with enlargement of the food vacuole and accumulation of undegraded hemoglobin, indicating inhibition of hemoglobin degradation by MG132, most likely due to inhibition of hemoglobin-degrading falcipain cysteine proteases. Parasites cultured with epoxomicin or MG132 accumulated ubiquitinated proteins to a significantly greater extent than untreated or E64-treated parasites, indicating that MG132 inhibits the parasite UPS as well. Consistent with these findings, MG132 inhibited both cysteine protease and UPS activities present in soluble parasite extracts, and it strongly inhibited recombinant falcipains. MG132 was highly selective for inhibition of P. falciparum (IC50 0.0476 µM) compared to human peripheral blood mononuclear cells (IC50 10.8 µM). Thus, MG132 inhibits two distinct proteolytic systems in P. falciparum, and it may serve as a lead molecule for development of dual-target inhibitors of malaria parasites.

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Section: Introductionmentioning

confidence: 99%

Blocking Plasmodium falciparum Development via Dual Inhibition of Hemoglobin Degradation and the Ubiquitin Proteasome System by MG132

et al. 2013

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“…Lico-A has been used for thousands of years as a traditional herbal medicine and is known for its multiple bioactivities including anti-inflammatory (1), anti-microbial (2), anti-malarial (3), and osteogenic activity (4), and anti-angiogenic (5) and anticancer effects (6–9). Moreover, Lico-A has also been suggested to be beneficial for common oro-dental disease via its anti-adhesion properties (10).…”

Section: Introductionmentioning

confidence: 99%

Licochalcone A induces apoptosis in KB human oral cancer cells via a caspase-dependent FasL signaling pathway

et al. 2013

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Licochalcone A (Lico-A) is a natural phenol licorice compound with multiple bioactivities, including anti-inflammatory, anti-microbial, anti-fungal and osteogenesis-inducing properties. In the present study, we investigated the Lico-A-induced apoptotic effects and examined the associated apoptosis pathway in KB human oral cancer cells. Lico-A decreased the number of viable KB oral cancer cells. However, Lico-A did not have an effect on primary normal human oral keratinocytes. In addition, the IC50 value of Lico-A was determined to be ~50 μM following dose-dependent stimulation. KB oral cancer cells stimulated with Lico-A for 24 h showed chromatin condensation by DAPI staining, genomic DNA fragmentation by agarose gel electrophoresis and a gradually increased apoptotic cell population by FACS analysis. These data suggest that Lico-A induces apoptosis in KB oral cancer cells. Additionally, Lico-A-induced apoptosis in KB oral cancer cells was mediated by the expression of factor associated suicide ligand (FasL) and activated caspase-8 and −3 and poly(ADP-ribose) polymerase (PARP). Furthermore, in the KB oral cancer cells co-stimulation with a caspase inhibitor (Z-VAD-fmk) and Lico-A significantly abolished the apoptotic phenomena. Our findings demonstrated that Lico-A-induced apoptosis in KB oral cancer cells involves the extrinsic apoptotic signaling pathway, which involves a caspase-dependent FasL-mediated death receptor pathway. Our data suggest that Lico-A be developed as a chemotherapeutic agent for the management of oral cancer.

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“…The intermediate used are substituted chalcones derived from various substituted aldehydes and ketones which are known for their anticancer [9], antioxidant [10], analgesic [11], anti-inflammatory [12], and antimalarial [13] activities. Based on the observations, it was contemplated to synthesize a novel series pyrazoline derivatives derived from substituted chalcones.…”

Section: Introductionmentioning

confidence: 99%

Pyrazolines as Potent Antitubercular and Cytotoxic Agents

Kumar

2017

Asian J Pharm Clin Res

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Objective: Pyrazolines are known to exhibit different biological and pharmacological properties such as anticancer, antibacterial, antifungal and antitubercular activities. Chalcones with an enone group between two aromatic rings exhibit remarkable pharmacological activities such as antiinflammatory, antibacterial, antitumor, antifungal, and antimalarial activity. A series of pyrazolines from chalcones have been synthesized and evaluated for antitubercular and cytotoxic activity studies.Methods: Chalcones [3-substituted phenyl-1-(p-tolyl)prop-2-en-1-one] were synthesized from various substituted aldehydes and 4-methyl acetophenone and cyclized into pyrazolines [5-substituted phenyl-3-(p-tolyl)-4,5-dihydro-1H-pyrazole] using hydrazine hydrate. Antitubercular and cytotoxic activity studies were carried out.Results: Antitubercular and cytotoxic activity studies of synthesized pyrazoline revealed that some compounds have showed promising activity. Conclusion:The observed results proved that pyrazolines are found to be interesting lead molecules for further synthesis as antitubercular and cytotoxic agents.

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Synthesis and Insight into the Structure–Activity Relationships of Chalcones as Antimalarial Agents

Cited by 88 publications

References 59 publications

Blocking Plasmodium falciparum Development via Dual Inhibition of Hemoglobin Degradation and the Ubiquitin Proteasome System by MG132

Blocking Plasmodium falciparum Development via Dual Inhibition of Hemoglobin Degradation and the Ubiquitin Proteasome System by MG132

Licochalcone A induces apoptosis in KB human oral cancer cells via a caspase-dependent FasL signaling pathway

Pyrazolines as Potent Antitubercular and Cytotoxic Agents

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