Heparin appended ADH-anionic polysaccharide nanoparticles for site-specific delivery of usnic acid.

The intention of present research work is to formulate usnic acid (UA) loaded heparin modified gellan gum (HAG) nanoparticles (NPs). HAG copolymer based conjugation was synthesized and characterized by 1H NMR and FT-IR spectroscopy. Plain and UA loaded HAG NPs were prepared via nanoprecipitation technique. NPs were typified and further characterized for particle size, polydispersity index, entrapment efficiency, zeta potential, atomic force microscopy, differential scanning calorimetry, X-ray diffraction analysis, and in-vitro release. In-vitro tube formation assay, tumorsphere assay, autophagy assay, DNA cleavage assay, internalization by confocal and FACS based internalization analysis, caspase assay and cell cycle assay were performed for biological activity. Obtained experimental results explored that HAG NPs displayed a sustained release of UA (95.67% in 48 h) compared to gellan gum NPs (96.12% in 8 h). In cytotoxicity studies, UA loaded HAG NPs exhibited an enormous cytotoxic potential against A549 cancer cells. In the in vivo bio-distribution study, using albino rat model the free UA concentration was found 7.09 ±â€¯0.9%, 2.7 ±â€¯1.5%, 7.5 ±â€¯2.1, 9.2 ±â€¯2%, and 6.25 ±â€¯1.3% post two hours of intravenous administration, however, in the case of UA loaded HAG NPs the obtained level was 4.1 ±â€¯1.10, 7.7 ±â€¯1.30%, 2.21 ±â€¯0.29%, 1.85 ±â€¯0.25%, 2.2 ±â€¯0.78%, 2.9 ±â€¯1.21% respectively, in heart, lung, liver, spleen, intestine and kidney. The overall anticancer study and result of internalization deciphered the higher anticancer potential of UA loaded HAG NPs.

Structural insight for imidazopyridazines as malarial kinase PfPK7 inhibitors using QSAR techniques.

With a view to the rational design of a selected series of 35 imidazopyridazine derivatives, 2D and 3D QSAR models have been developed for the prediction of antimalarial activity. The statistically best 2D QSAR model having r(2) = 0.9242 and q(2) = 0.8691 with pred_r(2) = 0.9206 was developed by SW-MLR and best 3D QSAR model having q(2) = 0.8607 with pred_r(2) = 0.8332 was developed by k-nearest neighbor molecular field analysis (kNN-MFA). Molecular docking study was also carried out to better understand of the interactions between PfPK7 enzyme target (pdb: 2pnm) and inhibitors in this series. The docking study suggests that these PfPK7 inhibitors interact with Met120, Lys55, Tyr117, Asp123, Leu179, Leu34, Asn35, Ala53, Glu88, Leu101, Tyr119, Ser124, Ser189 and Asp190 amino acid residues of protein PfPK7. Both QSAR and docking studies of such derivatives provide guidance for further lead optimization and designing of more potent PfPK7 inhibitors.

Qsar study of some substituted 4-quinolinyl and 9-acridinyl hydrazones as antimalarial agents.

The quantitative structure-activity relationship (QSAR) analysis of some synthesized substituted 4-quinolinyl and 9-acridinyl hydrazone derivatives were performed to find out the structural requirements of their antimalarial activities. Various 2D descriptors were calculated and used in the present analysis. The 2D-QSAR studies were performed using three statistical methods: the multiple linear regressions, giving square of correlation coefficient (r(2)) = 0.8456, cross validated squared correlation coefficient (q(2)) = 0.7814 and predictable ability (pred_r(2)) = 0.7443; the partial least squares regression, with r(2) = 0.8402, q(2) = 0.7879 and pred_r(2) = 0.7680; and principle component regression, giving r(2) = 0.8392, q(2) = 0.7979 and pred_r(2) = 0.6440. Best equation was selected on the basis of high r(2), q(2) and pred_r(2). The QSAR model indicated that the T_N_O_3, IdAverage, chiV6chain, Most-vePotential and T_C_N_6 played an important role in determining antimalarial activities. The results of the present study may be useful on the designing of more potent analogues as antimalarial agents.

Novel molecular targets for antimalarial drug development.

Malaria with one million deaths and about 500 million new cases reported annually is a challenge to drug therapy and discovery. As current antimalarial therapeutics become increasingly ineffective because of parasitic resistance, there exists an urgent need to develop and pursue new therapeutic strategies. Antimalarial drug development can follow several strategies, ranging from minor modifications of existing agents to the design of novel agents that act against new targets. Recent advances in our knowledge of parasite biology as well as the availability of the genome sequence provide a wide range of novel targets for drug design. Several promising targets for drug intervention have been revealed in recent years. This review discusses novel molecular targets of the malaria parasite available to the drug discovery scientist.