Synthesis and in vitro evaluation of imidazopyridazines as novel inhibitors of the malarial kinase PfPK7

Bouloc, Nathalie; Large, Jonathan M.; Smiljanic, Ela; Whalley, David; Ansell, Keith H.; Edlin, Christopher D.; Bryans, Justin S.

doi:10.1016/j.bmcl.2008.08.043

Cited by 37 publications

(25 citation statements)

References 16 publications

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“…Dataset A series of potent PfPK7 inhibitors (34 imidazopyridazine derivatives) with inhibitory activity were identified from the literature (Bouloc et al, 2008). The compounds were divided randomly into a training set (n = 26) and a test set (n = 8).…”

Section: Methodsmentioning

confidence: 99%

QSAR analysis on PfPK7 inhibitors using HQSAR, CoMFA, and CoMSIA

et al. 2011

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Plasmodium falciparum protein kinase 7 (PfPK7) is an important drug target for the development of anti-malarial treatment. In this study, hologram quantitative structure-activity relationship (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of imidazopyridazine derivatives of PfPK7 inhibitors. The best HQSAR model was obtained using atoms, connection, donor, and acceptor as fragment distinction parameter with fragment size (4-7) using a hologram length of 353 and 6 components (q 2 = 0.770, r 2 = 0.964). The receptor-guided alignment has produced better statistical results for both CoMFA (q 2 = 0.590, r 2 = 0.986) and CoMSIA (q 2 = 0.735, r 2 = 0.988). The predictive ability of the developed models was further validated by a test set of eight compounds. HQSAR contribution map identified the presence of phenyl ring and cyclohexane moiety makes positive contribution for activity. Furthermore, CoMFA and CoMSIA contour maps suggested that additional bulky groups in cyclohexane moiety would increase the biological activity of PfPK7 inhibitors. Finally, these QSAR models were used to design new virtual molecules for imidazopyridazine derivatives and the results obtained from this study could be useful for further investigations.

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Section: Methodsmentioning

confidence: 99%

QSAR analysis on PfPK7 inhibitors using HQSAR, CoMFA, and CoMSIA

et al. 2011

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“…Some of the "orphan" or "semi-orphan" Pf protein kinases (such as FIKK kinases) and the unique Pf protein kinases (such as calcium-dependent kinases) in signaling pathways could be good drug targets. However, there are only a few relatively early stage drug discovery programs that focus on Pf protein kinases [89][90][91][92][93][94].…”

Section: Kinase Inhibitorsmentioning

confidence: 99%

Road Towards New Antimalarials – Overview of the Strategies and their Chemical Progress

Nagle²,

Chatterjee³

2011

CMC

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Malaria is a major health and economic threat to about 40% of the world's population. The absence of effective vaccines and widespread resistance to many of the current antimalarials make this disease an urgent target for the scientific community. As a developing world disease, most of the efforts towards new drugs have been from academic and government supported projects. This has recently changed with the emergence of new funding mechanisms and public-private partnerships (PPP). The purpose of this review is to highlight the different approaches used to discover new antimalarial agents, including target-based approaches, derivatization of known antimalarial pharmacophores, drug repositioning from non-malaria indication and cell-based screening. Specific examples are provided to illustrate the pros and cons in the context of how to best address the ever-increasing drug resistance and how to cost-effectively identify new antimalarials. More attention is given to relatively mature programs that have gone through extensive SAR study, pharmacology and/or toxicity studies in the last ten years.

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“…In this study, a series of imidazopyridazines (Table 1) having inhibitory potency towards malarial kinase PfPK7 enzyme were used as the model data set [5]. Out of 35 molecules, 1 molecule was discarded for which the precise data was not available.…”

Section: Data Set For Analysismentioning

confidence: 99%

“…The imidazopyridazine compounds were reported to possess good P. falciparum protein kinase 7 (PfPK7) inhibitory activities [5,6]. PfPK7 is expressed at several stages of the parasite life cycle, including both the asexual and sexual stages in man and also in the mosquito, but has no human homologue.…”

Section: Introductionmentioning

confidence: 99%

QSAR studies on imidazopyridazine derivatives as PfPK7 inhibitors

Sahu

Shahi

Sharma

et al. 2011

Molecular Simulation

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Quantitative structure -activity relationship (QSAR) studies were carried out on a series of 35 recently synthesised imidazopyridazine derivatives to investigate the structural requirements of their inhibitory activity against malarial kinase, Plasmodium falciparum protein kinase 7 (PfPK7). Partial least square (PLS) methodology coupled with various feature selection methods, viz. stepwise (SW), genetic algorithm (GA) and simulated annealing, was applied to derive QSAR models which were further validated for statistical significance and predictive ability by internal and external validation. The statistically significant best 2D-QSAR model having correlation coefficient r 2 ¼ 0.9190 and cross-validated squared correlation coefficient q 2 ¼ 0.8575 with external predictive ability of pred_r 2 ¼ 0.7212 was developed by SW-PLS with the descriptors like StNE-index, T_N_O_2, T_N_O_7, YcompDipole and SaasCE-index. Molecular field analysis was used to construct the best 3D-QSAR model using GA-PLS method, showing good correlative and predictive capabilities in terms of q 2 ¼ 0.7494 and pred_r 2 ¼ 0.8841. The information rendered by 2D-and 3D-QSAR models may lead to a better understanding of structural requirements of PfPK7 inhibitors and also aid in designing novel potent antimalarial molecules.

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Synthesis and in vitro evaluation of imidazopyridazines as novel inhibitors of the malarial kinase PfPK7

Cited by 37 publications

References 16 publications

QSAR analysis on PfPK7 inhibitors using HQSAR, CoMFA, and CoMSIA

QSAR analysis on PfPK7 inhibitors using HQSAR, CoMFA, and CoMSIA

Road Towards New Antimalarials – Overview of the Strategies and their Chemical Progress

QSAR studies on imidazopyridazine derivatives as PfPK7 inhibitors

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