Chemometric modelling of antimalarial activity of aryltriazolylhydroxamates

We have performed quantitative structure–activity relationship (QSAR) and quantitative activity–activity relationship (QAAR) studies for aryltriazolylhydroxamates having antimalarial activity data against both chloroquine-sensitive (D6 clone) and chloroquine-resistant (W2 clone) strains of Plasmodium falciparum to understand the relationships between the biological activity and molecular properties for the design of new compounds. The QSAR studies were performed using 35 compounds among which 26 molecules were taken using k-means clustering technique in the training set for the derivation of the QSAR models and nine molecules were kept as the test-set compounds to evaluate the predictive ability of the derived models. The chemometric tool used for the analysis was the genetic function approximation. The developed models were analysed in terms of their predictive ability, and comparable results were obtained for cross-validated predictive variance (Q ²) and externally predicted variance (R ² _pred) values (0.761 and 0.829, respectively, for the D6 model, 0.708 and 0.748, respectively, for the W2 model and 0.984 and 0.982, respectively for the QAAR model). The QSAR models suggest that the number of methylene groups (between the triazolyl and hydroxamate moieties) and partially negatively charged surface areas of the molecules are important parameters for the antimalarial activity.     

Stereoelectronic features of the cinchona alkaloids determine their differential antimalarial activity.

For most potent antimalarial activity, the cinchona alkaloids appear to require certain electronic features, particularly a sufficiently acidic hydroxyl proton and an electric field direction pointing from the aliphatic nitrogen atom towards the quinoline ring. These observations are the result of an analysis of molecular electronic properties of eight cinchona alkaloids and an in vivo metabolite calculated using ab initio 3-21G quantum chemical methods in relation to their in vitro IC50 values against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum parasites. The purpose is to provide a profile of the electronic characteristics necessary for potent antimalarial activity for use in the design of new antimalarial agents and to gain insight into the mechanistic path for antimalarial activity. Distinguishing features of the weakly active epiquinine and epiquinidine include a higher dipole moment, a different direction of the electric field, a greater intrinsic nucleophilicity, lower acidity of the hydroxyl proton, a lesser electron affinity of the lowest unoccupied molecular orbitals, and a higher proton affinity than the active cinchona alkaloids. A moderately potent quinine metabolite possesses some, but not all, of the same electronic features as the most potent cinchona alkaloids. Both the positioning of the hydroxyl and aliphatic amine groups and their electronic features appear to play a crucial role for antimalarial potency of the cinchona alkaloids, most likely by controlling the ability of these groups to form effective intermolecular hydrogen bonds.     

Sulfonyl-phenyl-ureido benzamidines; a novel structural class of potent antimalarial agents

The high throughput in silico screening of a virtual library into the structure of the P. falciparum lactate dehydrogenase (LDH) with the 4SCan technology yielded a series of biphenyl urea compounds. These were chemically optimized to a new structural class of potent antimalarial agents. The compounds did not inhibit plasmodium LDH enough to fully explain their potency. Therefore we conclude that an unknown mode of action may be the cause of the antimalarial activity.     

3D QSAR,pharmacophore and molecular docking studies of known inhibitors and designing of novel inhibitors for M18 aspartyl aminopeptidase of <Emphasis Type="Italic">Plasmodium falciparum</Emphasis>

Background

The Plasmodium falciparum M18 Aspartyl Aminopeptidase (PfM18AAP) is only aspartyl aminopeptidase which is found in the genome of P. falciparum and is essential for its survival. The PfM18AAP enzyme performs various functions in the parasite and the erythrocytic host such as hemoglobin digestion, erythrocyte invasion, parasite growth and parasite escape from the host cell. It is a valid target to develop antimalarial drugs. In the present work, we employed 3D QSAR modeling, pharmacophore modeling, and molecular docking to identify novel potent inhibitors that bind with M18AAP of P. falciparum.

Results

The PLSR QSAR model showed highest value for correlation coefficient r² (88 %) and predictive correlation coefficient (pred_r2) =0.6101 for external test set among all QSAR models. The pharmacophore modeling identified DHRR (one hydrogen donor, one hydrophobic group, and two aromatic rings) as an essential feature of PfM18AAP inhibitors. The combined approach of 3D QSAR, pharmacophore, and structure-based molecular docking yielded 10 novel PfM18AAP inhibitors from ChEMBL antimalarial library, 2 novel inhibitors from each derivative of quinine, chloroquine, 8-aminoquinoline and 10 novel inhibitors from WHO antimalarial drugs. Additionally, high throughput virtual screening identified top 10 compounds as antimalarial leads showing G-scores -12.50 to -10.45 (in kcal/mol), compared with control compounds(G-scores -7.80 to -4.70) which are known antimalarial M18AAP inhibitors (AID743024). This result indicates these novel compounds have the best binding affinity for PfM18AAP.

Conclusion

The 3D QSAR models of PfM18AAP inhibitors provided useful information about the structural characteristics of inhibitors which are contributors of the inhibitory potency. Interestingly, In this studies, we extrapolate that the derivatives of quinine, chloroquine, and 8-aminoquinoline, for which there is no specific target has been identified till date, might show the antimalarial effect by interacting with PfM18AAP.

     

Second-generation antimalarial endoperoxides

Artemisinin, derived from a Chinese herbal remedy, is a potent peroxide-containing antimalarial. New types of peroxides, derived from this structure, as well as other naturally occurring antimalarial peroxides, have been synthesized and found to have potent antimalarial activities. Studies on the activities, modes of action, and toxicities of these compounds are discussed here by Steven Meshnick and colleagues.