Kashyap, et al.: Antimalarial Activity of Quinoline-Lawsone HybridsIn the present study, a new series of quinoline-lawsone hybrid compounds were synthesized and evaluated in vitro for their antimalarial effectiveness. Several aliphatic and aromatic/heteroaromatic diamines were used as connecting/bridge moiety between the 7-chloro-4-aminoquinoline and 3-amino-1, 4-naphthoquinone pharmacophoric scaffolds. The molecular properties of hybrid compounds were also studied in silico for drug-likeness assessment based on Lipinski's rule of five. Results of antimalarial activity reveal that all the tested compounds showed activity against both chloroquine sensitive (RKL-2) and chloroquine resistant (RKL-9) strains of Plasmodium falciparum which was considerably less as compared to the standard drug, chloroquine. All the compounds exhibited same degree of activity at the tested dose against sensitive strain with IC 50 values 0.391-1.033 µg/ml. Furthermore, four compounds which were additionally tested against resistant strain also showed activity with IC 50 values from 0.684 to 1.778 µg/ml at the same dose. The IC 50 values for CQ against sensitive and resistant strains of P. falciparum were found to be 0.0391 µg/ml and 0.305 µg/ml, respectively. From results it is apparent that the compound with a small alkyl bridge moiety diaminoethyl possesses better activity profile against both sensitive and resistant strains (IC 50 =0.391 and 0.684 µg/ml, respectively) than rest of the synthesized analogues. The results of drug-likeness studies showed that all newly designed quinoline-lawsone hybrids possess good drug-like properties, indicating their druglikeness behaviour is favourable for optimal antimalarial action. Assessment of drug-likeness score further implies the suitability of hybrid derivatives as drug-like molecules.Key words: Quinoline, lawsone, hybrid, bridge moiety, Plasmodium falciparum, resistant malariaOver the last few decades, the burden of malaria has increasingly become a serious health concern around the globe. The disease remains one of the most lethal infectious diseases of human beings affecting around 300-600 million people with about three million deaths per year globally [1] . Plasmodium falciparum is the most prevalent and deadly species among all malaria parasites, which causes severe complicated malaria such as cerebral malaria, and is responsible for most of the malaria-related deaths worldwide. Recent emergence of multidrug-resistant strains of P. falciparum has further complicated the issues of treating malaria using currently available antimalarial drugs [2][3][4] . However, with the development of novel and potent antimalarial agents the above challenging issue could be addressed.Chloroquine (CQ, fig. 1), a 4-aminoquinoline synthetic antimalarial, was once a highly potent drug against malaria. Literature reports suggest that 7-chloro-4-aminoquinoline nucleus of 4-aminoquinoline antimalarial drugs is responsible for their antimalarial action which could be attributed mainly due to the prevention o...

This particular study certainly benefits the researchers interested in exploiting the antibacterial activity of thiazoles in search of novel agents.

A series of novel PABA‐substituted 1,3,5‐triazine derivatives were developed via microwave assisted synthesis and subsequently tested for antimalarial activity against chloroquine sensitive 3D7 strain of Plasmodium falciparum using chloroquine as standard. Antimalarial screening result showed that synthesized compounds exhibited IC50 in the range of 4.46 to 79.72 μg mL−1. Among the tested compounds, 4c and 4f showed significant antimalarial activity with low binding energies (BE) ‐172.32 and 160.41 kcal mol−1 via interacting with Arg122 through the involvement of COOH of the phenyl linked to 1,3,5‐triazine. In conclusion, these core scaffolds can be used for future antimalarial drug development.

Background: Presentlytheeffectiveness of antifolate antimalarial drugs is decreasing due to the emergence of resistant Plasmodium strains. The aim of the present study was to determine the antimalarial effect of hybrid p-bromo phenyl thiazole-triazine derivatives against 3D7 strain of Plasmodium falciparum. Methods: Seventy-fivehybrid derivativeswere designed based on the lead molecule and docking was done against the active site of Pf-DHFR-TS (PDB i.d. 1J3i) with validated ligand fit protocol by using Discovery Studio 2.5. Based on the highest binding energy and the best docked pose, fifteen compounds were selected for the synthesis. Synthesized compounds were characterized by different spectroscopy methods and in-vitro antimalarial evaluation was done against the 3D7 strain of Plasmodium falciparum. Results: Fifteen compounds were synthesized by conventional and microwave assisted method and were characterized byFT-IR, 1H-NMR, 13C-NMR and Mass spectroscopy. In-vitro antimalarial screening results showed that compounds ADG303, ADG 306 and ADG 302 have the highest activity against 3D7 strain of P. falciparum. Furthermore, docking result of these compounds having binding energies of -154.91, -165.981, -137.826 respectively showed similarity with reference compound WR99210 (-152.023) and also bound to Asp54 and Phe 58 amino acid at the active site of the receptor. Conclusion: The synthesized compound ADG303 exhibited an encouraging result which could be a new lead for antimalarial drug discovery.

The present manuscript deals with the development of novel p-aminobenzoic acid (PABA) associated 1,3,5-triazine derivatives as antimalarial agents. The molecules were developed via microwave-assisted synthesis and structures of compounds were ascertained via numerous analytical and spectroscopic techniques. The synthesized compounds were also subjected to ADMET analysis. In a docking analysis, the title compounds showed high and diverse binding affinities towards wild (−162.45 to −369.38 kcal/mol) and quadruple mutant (−165.36 to −209.47 kcal/mol) Pf-DHFR-TS via interacting with Phe58, Arg59, Ser111, Ile112, Phe116. The in vitro antimalarial activity suggested that compounds 4e, 4b, and 4h showed IC 50 ranging from 4.18 to 8.66 μg/ml against the chloroquine-sensitive (3D7) strain of Plasmodium falciparum. Moreover, compounds 4g, 4b, 4e, and 4c showed IC 50 ranging from 8.12 to 12.09 μg/ml against chloroquine-resistant (Dd2) strain. In conclusion, our study demonstrated the development of hybrid PABA substituted 1,3,5-triazines as a novel class of Pf-DHFR inhibitor for antimalarial drug discovery.