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Discovery of a selective, safe and novel anti-malarial compound with activity against chloroquine resistant strain of Plasmodium falciparum.

Agarwal A, Paliwal S, Mishra R, Sharma S, Kumar Dwivedi A, Tripathi R, Gunjan S - Sci Rep (2015)

Bottom Line: A rigorously validated pharmacophore model comprising of two positive ionizable (PI), one hydrophobic (HY) and one ring aromatic (RA) features was used to mine NCI chemical compound database.This led to retrieval of many hits which were screened on the basis of estimated activity, fit value and Lipinski's violation.The results revealed that out of two, NSC639017 posses excellent anti-malarial activity particularly against chloroquine resistant strain and moreover NSC639017 also appeared to be safe (CC50 126.04 μg/ml) and selective during cytotoxicity evaluation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Banasthali University, Rajasthan, 304022, India.

ABSTRACT
In recent years the DNA minor groove has attracted much attention for the development of anti-malarial agents. In view of this we have attempted to discover novel DNA minor groove binders through in-silico and in-vitro workflow. A rigorously validated pharmacophore model comprising of two positive ionizable (PI), one hydrophobic (HY) and one ring aromatic (RA) features was used to mine NCI chemical compound database. This led to retrieval of many hits which were screened on the basis of estimated activity, fit value and Lipinski's violation. Finally two compounds NSC639017 and NSC371488 were evaluated for their in-vitro anti-malarial activities against Plasmodium falciparum 3D7 (CQ sensitive) and K1 (CQ resistant) strains by SYBR green-I based fluorescence assay. The results revealed that out of two, NSC639017 posses excellent anti-malarial activity particularly against chloroquine resistant strain and moreover NSC639017 also appeared to be safe (CC50 126.04 μg/ml) and selective during cytotoxicity evaluation.

No MeSH data available.


Related in: MedlinePlus

(a) Pharmacophore mapping of the most active training set compound 13a, (b) Pharmacophore mapping of the least active training set compound 36b.
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f1: (a) Pharmacophore mapping of the most active training set compound 13a, (b) Pharmacophore mapping of the least active training set compound 36b.

Mentions: During mapping of training set compounds it was observed that most active compound 13a (IC50 0.002 μM) of training set mapped well over the model with a fit value of 8.027. Both the positive ionizable (PI) features mapped over the two guanidine moieties present at the terminal position. One ring aromatic (RA) feature mapped on to the benzene ring while hydrophobic feature mapped on to another benzene ring (Fig. 1a). On the other hand least active compound 36b (IC50 17.1 μM) with a poor fit value of 4.671 clearly missed one RA and PI features during mapping (Fig. 1b).


Discovery of a selective, safe and novel anti-malarial compound with activity against chloroquine resistant strain of Plasmodium falciparum.

Agarwal A, Paliwal S, Mishra R, Sharma S, Kumar Dwivedi A, Tripathi R, Gunjan S - Sci Rep (2015)

(a) Pharmacophore mapping of the most active training set compound 13a, (b) Pharmacophore mapping of the least active training set compound 36b.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561909&req=5

f1: (a) Pharmacophore mapping of the most active training set compound 13a, (b) Pharmacophore mapping of the least active training set compound 36b.
Mentions: During mapping of training set compounds it was observed that most active compound 13a (IC50 0.002 μM) of training set mapped well over the model with a fit value of 8.027. Both the positive ionizable (PI) features mapped over the two guanidine moieties present at the terminal position. One ring aromatic (RA) feature mapped on to the benzene ring while hydrophobic feature mapped on to another benzene ring (Fig. 1a). On the other hand least active compound 36b (IC50 17.1 μM) with a poor fit value of 4.671 clearly missed one RA and PI features during mapping (Fig. 1b).

Bottom Line: A rigorously validated pharmacophore model comprising of two positive ionizable (PI), one hydrophobic (HY) and one ring aromatic (RA) features was used to mine NCI chemical compound database.This led to retrieval of many hits which were screened on the basis of estimated activity, fit value and Lipinski's violation.The results revealed that out of two, NSC639017 posses excellent anti-malarial activity particularly against chloroquine resistant strain and moreover NSC639017 also appeared to be safe (CC50 126.04 μg/ml) and selective during cytotoxicity evaluation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Banasthali University, Rajasthan, 304022, India.

ABSTRACT
In recent years the DNA minor groove has attracted much attention for the development of anti-malarial agents. In view of this we have attempted to discover novel DNA minor groove binders through in-silico and in-vitro workflow. A rigorously validated pharmacophore model comprising of two positive ionizable (PI), one hydrophobic (HY) and one ring aromatic (RA) features was used to mine NCI chemical compound database. This led to retrieval of many hits which were screened on the basis of estimated activity, fit value and Lipinski's violation. Finally two compounds NSC639017 and NSC371488 were evaluated for their in-vitro anti-malarial activities against Plasmodium falciparum 3D7 (CQ sensitive) and K1 (CQ resistant) strains by SYBR green-I based fluorescence assay. The results revealed that out of two, NSC639017 posses excellent anti-malarial activity particularly against chloroquine resistant strain and moreover NSC639017 also appeared to be safe (CC50 126.04 μg/ml) and selective during cytotoxicity evaluation.

No MeSH data available.


Related in: MedlinePlus