Synthesis and evaluation of phenoxyoxazaphospholidine, phenoxyoxazaphosphinane, and benzodioxaphosphininamine sulfides and related compounds as potential anti-malarial agents

Mara, Christine; Dempsey, Enda; Bell, Angus; Barlow, James W.

doi:10.1016/j.bmcl.2013.04.026

Cited by 7 publications

(2 citation statements)

References 17 publications

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“…Developing a potent antimalarial compound is still a major challenge for the medicinal chemists (Biamonte et al, 2013). The situation is worsening with the rapid spread of multi drug resistant strains of causative agent (Biamonte et al, 2013;Mahajan et al, 2012;2013;Mara et al, 2013;Masand et al, 2013b;Murugesan et al, 2013;Ojha and Roy, 2012;Papireddy et al, 2011). Therefore, there is essential need to curb this deadly disease either by modifying the existing marketed drugs or developing new therapeutic molecules.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, there is essential need to curb this deadly disease either by modifying the existing marketed drugs or developing new therapeutic molecules. Different compounds like xanthones, artemisinins, prodiginines have been synthesized and tested to develop new potential remedies for malaria (Biamonte et al, 2013;Mahajan et al, 2012;2013;Mara et al, 2013;Masand et al, 2013b;Murugesan et al, 2013;Ojha and Roy, 2012;Papireddy et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Determination of Optimum Values of Descriptors to Set Filters for Synthetic Tri-Pyrrole Derivatives (Prodiginines) Against Multi Drug Resistant Strain of <i>Plasmodium Falciparum</i>

Masand¹,

Mahajan²,

Pourbasheer³

et al. 2014

Current Research in Drug Discovery

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In the present study, we have carried out extensive non-linear Quantitative-Structure Activity Relationship (QSAR) analysis to correlate in vitro anti-malarial activity against multi drug resistant strain of Plasmodium falciparum. Forty-three synthetic prodiginines with different structural features were used for their potential antimalarial activity. Linear, bilinear, biexponential and parabolic equations were developed. These equations were compared to determine the optimum values of descriptors for very useful and easily interpretable descriptors. The optimum values of these descriptors could be helpful in finding and optimizing a good lead compound. Obtained correlations reveal that various factors like lipophilicity, molecular weight and number of bonds have non-linear relation with the anti-malarial activity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Determination of Optimum Values of Descriptors to Set Filters for Synthetic Tri-Pyrrole Derivatives (Prodiginines) Against Multi Drug Resistant Strain of <i>Plasmodium Falciparum</i>

Masand¹,

Mahajan²,

Pourbasheer³

et al. 2014

Current Research in Drug Discovery

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Tautomerism and multiple modelling enhance the efficacy of QSAR: antimalarial activity of phosphoramidate and phosphorothioamidate analogues of amiprophos methyl

et al. 2014

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In the present study, sixty phosphoramidate and phosphorothioamidate analogues of amiprophos methyl (APM) previously reported as potential antimalarial agents were selected to build GA-MLR QSAR models to determine the features that govern the antimalarial activity. In addition, field similarity analysis was performed to determine the molecular fields that are responsible for the difference in the activity. The two tautomeric forms, possible for the molecules in the present study, were considered to determine the effect of tautomerism on QSAR modelling. In the present analysis, a simplistic approach was employed with the assumption that all the molecules either exist in keto-type tautomeric form or in enol-type form. To get more results from QSAR analysis, multiple models were developed. All the models have been thoroughly validated according to the OECD principles. The best four-parametric GA-MLR QSAR model is with R2 = 0.787 and Rex2 = 0.806 for the keto form, and R2 = 0.785 and Rex2 = 0.770 for the enol form. In addition, optimum values for more easily interpretable descriptors like molecular weight (MW), lipophilicity (ALogP), etc., have been determined. The analysis reveals that consideration of tautomerism and multiple models development enhance the efficiency of QSAR analysis for lead optimization and for prediction of the activities of as-yet untested molecules

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New insight-guided approaches to detect, cure, prevent and eliminate malaria

2014

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New challenges posed by the development of resistance against artemisinin-based combination therapies (ACTs) as well as previous first-line therapies, and the continuing absence of vaccine, have given impetus to research in all areas of malaria control. This review portrays the ongoing progress in several directions of malaria research. The variants of RTS,S and apical membrane antigen 1 (AMA1) are being developed and test adapted as multicomponent and multistage malaria control vaccines, while many other vaccine candidates and methodologies to produce antigens are under experimentation. To track and prevent the spread of artemisinin resistance from Southeast Asia to other parts of the world, rolling circle-enhanced enzyme activity detection (REEAD), a time- and cost-effective malaria diagnosis in field conditions, and a DNA marker associated with artemisinin resistance have become available. Novel mosquito repellents and mosquito trapping and killing techniques much more effective than the prevalent ones are undergoing field testing. Mosquito lines stably infected with their symbiotic wild-type or genetically engineered bacteria that kill sympatric malaria parasites are being constructed and field tested for stopping malaria transmission. A complementary approach being pursued is the addition of ivermectin-like drug molecules to ACTs to cure malaria and kill mosquitoes. Experiments are in progress to eradicate malaria mosquito by making it genetically male sterile. High-throughput screening procedures are being developed and used to discover molecules that possess long in vivo half life and are active against liver and blood stages for the fast cure of malaria symptoms caused by simple or relapsing and drug-sensitive and drug-resistant types of varied malaria parasites, can stop gametocytogenesis and sporogony and could be given in one dose. Target-based antimalarial drug designing has begun. Some of the putative next-generation antimalarials that possess in their scaffold structure several of the desired properties of malaria cure and control are exemplified by OZ439, NITD609, ELQ300 and tafenoquine that are already undergoing clinical trials, and decoquinate, usnic acid, torin-2, ferroquine, WEHI-916, MMV396749 and benzothiophene-type N-myristoyltransferase (NMT) inhibitors, which are candidates for future clinical usage. Among these, NITD609, ELQ300, decoquinate, usnic acid, torin-2 and NMT inhibitors not only cure simple malaria and are prophylactic against simple malaria, but they also cure relapsing malaria.

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Synthesis and evaluation of phenoxyoxazaphospholidine, phenoxyoxazaphosphinane, and benzodioxaphosphininamine sulfides and related compounds as potential anti-malarial agents

Cited by 7 publications

References 17 publications

Determination of Optimum Values of Descriptors to Set Filters for Synthetic Tri-Pyrrole Derivatives (Prodiginines) Against Multi Drug Resistant Strain of <i>Plasmodium Falciparum</i>

Determination of Optimum Values of Descriptors to Set Filters for Synthetic Tri-Pyrrole Derivatives (Prodiginines) Against Multi Drug Resistant Strain of <i>Plasmodium Falciparum</i>

Tautomerism and multiple modelling enhance the efficacy of QSAR: antimalarial activity of phosphoramidate and phosphorothioamidate analogues of amiprophos methyl

New insight-guided approaches to detect, cure, prevent and eliminate malaria

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