Synthesis and in vitro evaluation of hydrazinyl phthalazines against malaria parasite, Plasmodium falciparum

Subramanian, Gomathy Sandhya; Rajeev, C P Babu; Mohan, Chakrabhavi Dhananjaya; Sinha, Ameya; Chu, Trang T. T.; Anusha, Sebastian; Huang, Xiucai; Fuchs, Julian E.; Bender, Andreas; Rangappa, Kanchugarakoppal S.; Chandramohanadas, Rajesh; Basappa, Basappa

doi:10.1016/j.bmcl.2016.05.049

Cited by 28 publications

(17 citation statements)

References 27 publications

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“…Parasites were maintained in 2.5% hematocrit in RPMI-HEPES medium at pH 7.4 supplemented with hypoxanthine 50 µg mL −1 , NaHCO 3 25 mM, gentamicin 2.5 µg mL −1 , and Albumax II (Gibco) 0.5% wt/vol. Schizonts (∼ 45 hpi) were enriched using MACS (Miltenyi Biotech, Germany) followed by selection of rings by 5% sorbitol 23 .…”

Section: Methodsmentioning

confidence: 99%

Reticulocyte Infection Leads to Altered Behaviour, Drug Sensitivity and Host Cell Remodelling byPlasmodium falciparum

Chandramohanadas

Naidu²,

Chu³

et al. 2019

Preprint

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29Plasmodia are host-specific, both at the organism and cellular levels. During asexual 30 development, Plasmodium spp. infect cells of erythroid lineage, with an overall 31 propensity towards reticulocytes. This applies to even Plasmodium (P.) falciparum, the 32 most common causative agent of human malaria, implications of which remain 33 unexplored. Herein, for the first time, we characterize the developmental stages and 34 features of P. falciparum cultured in vitro in young reticulocytes (CD71 + ) in comparison to 35 standard normocyte (CD71 -) cultures. We demonstrate that there are notable differences 36 in the patterns of invasion, development and sensitivity to potent antimalarials (such as 37 artemisinin and dihydroartemisinin) for parasites residing in CD71 + reticulocytes. 38Through a transcriptomic approach, we report that P. falciparum parasites are able to 39 sense the host cell environment, and calibrate their metabolic and host cell remodelling 40 pathways through differential gene expression. These results form an exciting avenue on 41 which hitherto unexplored interactions between Plasmodium spp and different stages of 42 host red blood cells could be investigated in the broader contexts of drug resistance, 43 host tropism and zoonosis. 45Author Summary 46Parasites causing malaria infect red blood cells for development and proliferation during 47 asexual development. This asexual erythrocytic stage determines higher parasite 48 densities and eventual disease manifestation. Although the most virulent species of 49 Plasmodium infecting humans known as Plasmodium falciparum is able to infect red 50 blood cells of all ages, these parasites show a preference for younger blood cells. Of 51 note, the biochemical and biophysical properties of young and adult red blood cells vary 52 significantly. Herein, we undertook a comparative profiling of invasion process, parasite 53 development and drug response of Plasmoddium falciparum in two host cells: young red 54 blood cells (reticulocytes) and mature red blood cells (normocytes). We demonstrate that 55 P. falciparum infects human reticulocytes with higher affinity and demonstrate differential 56 3 sensitivity to drugs such as artemisinin while they reside within reticulocytes. 57Furthermore, we show that P. falciparum is able to detect differences in host 58 environment and adapt to it by changing the expression of genes required for host cell 59 remodelling. 61 Introduction 62Plasmodium infection and associated mortality remain an important concern to the 63 developing world with 218 million malaria cases and ~450,000 deaths annually 1 64 (https://www.who.int/malaria/publications/world-malaria-report-2018/en/). 65Widespread drug-resistance 2-3 and evolution of newer phenotypes; influenced by factors 66 such as changing availability and distribution of insect vector 4 , haematological 67 malignancies(1, 2) 5-6 (thalassemia, sickle cell anaemia, G6PD deficiency etc), providing 68 protective immunity to certain populations 7 , adversely impact malaria eradic...

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Section: Methodsmentioning

confidence: 99%

Reticulocyte Infection Leads to Altered Behaviour, Drug Sensitivity and Host Cell Remodelling byPlasmodium falciparum

Chandramohanadas

Naidu²,

Chu³

et al. 2019

Preprint

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“…Flow cytometry was performed using the Accuri C6 instrument (BD Biosciences), and 100,000 events was recorded and analyzed for deriving parasitemia and parasite stage transition data. Statistical analysis of the data was performed using GraphPad Prism (GraphPad Software, Inc.) 19 .…”

Section: Methodsmentioning

confidence: 99%

Whole Cell Phenotypic Screening Of MMV Pathogen Box identifies Specific Inhibitors of Plasmodium falciparum merozoite maturation and egress

Patra

Hingamire

Belekar

et al. 2019

Preprint

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30We report a systematic, cellular phenotype-based antimalarial screening of the MMV Pathogen Box 31 collection, which facilitated the identification of specific blockers of late stage intraerythrocytic 32 Plasmodium falciparum maturation. First, from standard growth inhibition asays, we discovered 62 33 additional antimalarials (EC 50 ≤ 10µM) over previously known antimalarial candidates from Pathogen 34 Box. A total of 90 potent molecules (EC 50 ≤ 1µM) were selected for evaluating their stage-specific 35 effects during the intra-erythrocytic development of P. falciparum. None of these molecules had 36 significant effect on ring-trophozoite transition, 10 molecules inhibited trophozoite-schizont transition, 37 and 21 molecules inhibited schizont-ring transition at 1µM. These compounds were further validated 38 in secondary assays by flow cytometry and microscopic imaging of treated cells to prioritize 12 39 molecules as potent and selective blockers of schizont-ring transition. Seven of these were found to 40 strongly inhibit calcium ionophore induced egress of Toxoplasma gondii, a related apicomplexan 41 parasite, suggesting that the inhibitors may be acting via similar mechanism in the two parasites, 42 which can be further exploited for target identification studies. Two of these molecules, with previously 43 unknown mechanism of action, MMV020670 and MMV026356, were found to induce fragmentation of 44 DNA in developing merozoites. Further mechanistic studies would facilitate therapeutic exploitation of 45 these molecules as broadly active inhibitors targeting development and egress of apicomplexan 46 parasites relevant to human health. 47 48 49 Despite technological advancements and improved knowledge on disease manifestation and 69 pathogen biology, progress in therapeutic development has been slower than expected for human 70 infectious diseases affecting the developing world. In addition to limited financial prospects, 71 pharmaceutical companies remain under significant pressure to address high attrition rates. In this 72 context, repurposing of old drugs is becoming a viable alternative through the exploitation of known 73 compounds with established mechanisms thereby shortening the time window between efficacy 74 testing to pharmacophore optimization 1-3 to eventual application. In recent efforts to speed up the 75 process of drug development against various pathogenic diseases, a collaborative model of public-76 private partnerships (PPPs) facilitated through Medicines for Malaria Venture (MMV: mmv.org) was 77 formed. This resulted in well-characterized drug-like small molecule libraries being made accessible 78 to academics worldwide, for the purpose of identifying novel bioactivities against various tropical 79 disease pathogens and conducting focused mechanistic studies. In 2015, the consortium launched 80 the open access "Pathogen Box" consisting of 400 drug-like small molecules, included 26 reference 81 compounds, with confirmed bioactivity against at least one of the neglected disease pathogens ...

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“…Discovery Studio 2.5 software from Accelrys was used for docking and visualization of the results as described earlier [51,52]. Initially, we obtained the crystal structure of the STAT3 homodimer bound to DNA (PDB ID: 1BG1) [53], cleaned, minimized the energy, and identified the spatial region of STAT3.…”

Section: In Silico Interaction Analysismentioning

confidence: 99%

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

et al. 2019

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STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented.In this report, we performed high-throughput virtual screening in search of STAT3 signaling inhibitors using a cheminformatics platform and identified 2-Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) as the inhibitor of the STAT3 signaling pathway. The predicted hit was evaluated in non-small cell lung cancer (NSCLC) cell lines for its STAT3 inhibitory activity. In vitro experiments suggested that ACHP decreased the cell viability and inhibited the phosphorylation of STAT3 on Tyr705 of NSCLC cells. In addition, ACHP imparted inhibitory activity on the constitutive activation of upstream protein tyrosine kinases, including JAK1, JAK2, and Src. ACHP decreased the nuclear translocation of STAT3 and downregulated its DNA binding ability. Apoptosis was evidenced by cleavage of caspase-3 and PARP with the subsequent decline in antiapoptotic proteins, including Bcl-2, Bcl-xl, and survivin. Overall, we report that ACHP can act as a potent STAT3 signaling inhibitor in NSCLC cell lines.

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Synthesis and in vitro evaluation of hydrazinyl phthalazines against malaria parasite, Plasmodium falciparum

Cited by 28 publications

References 27 publications

Reticulocyte Infection Leads to Altered Behaviour, Drug Sensitivity and Host Cell Remodelling byPlasmodium falciparum

Reticulocyte Infection Leads to Altered Behaviour, Drug Sensitivity and Host Cell Remodelling byPlasmodium falciparum

Whole Cell Phenotypic Screening Of MMV Pathogen Box identifies Specific Inhibitors of Plasmodium falciparum merozoite maturation and egress

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

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