Development, characterization, and evaluation of withaferin-A and artesunate-loaded pH-responsive acetal-dextran polymeric nanoparticles for the management of malaria.

Artemisinin and its derivatives have been commonly used to treat malaria. However, the emergence of resistance against artemisinin derivatives has posed a critical challenge in malaria management. In the present study, we have proposed a combinatorial approach, utilizing pH-responsive acetal-dextran nanoparticles (Ac-Dex NPs) as carriers for the delivery of withaferin-A (WS-3) and artesunate (Art) to improve treatment efficacy of malaria. The optimized WS-3 and Art Ac-Dex NPs demonstrated enhanced pH-responsive release profiles under parasitophorous mimetic conditions (pH 5.5). Computational molecular modeling reveals that Ac-Dex's polymeric backbone strongly interacts with merozoite surface protein-1 (MSP-1), preventing erythrocyte invasion. In-vitro antimalarial activity of drug-loaded Ac-Dex NPs reveals a 1-1.5-fold reduction in IC50 values compared to pure drug against the 3D7 strain of Plasmodium falciparum. Treatment with WS-3 Ac-Dex NPs (100 mg/kg) and Art Ac-Dex NPs (30 mg/kg) to Plasmodium berghei-infected mice resulted in 78.11 % and 100 % inhibition of parasitemia. Notably, the combination therapy comprised of Art and WS-3 Ac-Dex NPs achieved complete inhibition of parasitemia even at a half dose of Art, indicating the synergistic potential of the combinations. However, further investigations are necessary to confirm the safety and effectiveness of WS-3 and Art Ac-Dex NPs for their successful clinical implications.

Structure based drug design and fragment based approach to identify potential methotrexate analogues as dual inhibitors for management of psoriasis.

Psoriasis is characterized as chronic inflammatory disorder of skin having unregulated hyperproliferation and shedding of plaques. As per first line treatment methotrexate is the most widely used cytotoxic drug for psoriasis. It shows anti-proliferative effect with hDHFR while anti-inflammatory and immunosuppressive action is due to AICART. Serious hepatotoxic effects are recognized with long-term treatment of methotrexate. In this study, in silico technique is used in this work to find Dual-Acting Methotrexate-like molecules with increased efficacy and decreased toxicity. Structure-based virtual screening assisted by a fragment-based method against a library of chemicals that are similar to methotrexate revealing 36 and 27 potential inhibitors of hDHFR and AICART respectively. Further, based on dock score, binding energy, molecular interactions, and ADME/T analysis compound 135565151 was chosen for dynamic stability evaluation. Overall, these findings provided information on possible methotrexate analogues for the treatment of psoriasis that had lower hepatotoxicity.Communicated by Ramaswamy H. Sarma.