Drug Repurposing of Quisinostat to Discover Novel HDAC1 Inhibitors with Enhanced Triple-Stage Antimalarial Activity and Improved Safety.

Our previous work found that the clinical histone deacetylase (HDAC) inhibitor quisinostat exhibited a significant antimalarial effect but with severe toxicity. In this work, 35 novel derivatives were designed and synthesized based on quisinostat as the lead compound, and their in vitro antimalarial activities and cytotoxicities were systematically evaluated. Among them, showed potent inhibition against both wild-type and multidrug-resistant parasite strains and displayed a significant in vivo killing effect against all life cycles of parasites, including the blood stage, liver stage, and gametocyte stage, indicating its potential for the simultaneous treatment, chemoprevention, and blockage of malaria transmission.

Discovery of Novel HDAC1 Inhibitors with Dual-Stage Antimalarial Potency and Improved Safety Based on the Clinical Anticancer Drug Candidate Quisinostat.

Previously, we identified the clinical anticancer drug candidate quisinostat as a novel and potent antimalarial lead compound. To further enhance the antimalarial effect and improve safety, 31 novel spirocyclic hydroxamic acid derivatives were synthesized based on the structure of quisinostat, and their antimalarial activities and cytotoxicity were evaluated. Among them, compound displayed broad potency against several multiresistant malarial parasites, especially two artemisinin-resistant clinical isolates.

A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1.

Although artemisinin combination therapies have succeeded in reducing the global burden of malaria, multidrug resistance of the deadliest malaria parasite, Plasmodium falciparum, is emerging worldwide. Innovative antimalarial drugs that kill all life-cycle stages of malaria parasites are urgently needed. Here, we report the discovery of the compound JX21108 with broad antiplasmodial activity against multiple life-cycle stages of malaria parasites.

Novel Tadalafil Derivatives Ameliorates Scopolamine-Induced Cognitive Impairment in Mice via Inhibition of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5).

On the basis of the drug-repositioning and redeveloping strategy, first-generation dual-target inhibitors of acetylcholinesterase (AChE) and phosphodiesterase 5 (PDE5) have been recently reported as a potentially novel therapeutic method for the treatment of Alzheimer's disease (AD), and the lead compound 2 has proven this method was feasible in AD mouse models. In this study, our work focused on exploring alternative novel tadalafil derivatives (3a-s). Among the 19 analogues, compound 3c exhibited good selective dual-target AChE/PDE5 inhibition and good blood-brain barrier (BBB) permeability.

Novel Staphyloxanthin Inhibitors with Improved Potency against Multidrug Resistant .

Diapophytoene desaturase (CrtN) is a potential novel target for intervening in the biosynthesis of the virulence factor staphyloxanthin. In this study, 38 1,4-benzodioxan-derived CrtN inhibitors were designed and synthesized to overwhelm the defects of leading compound . Derivative displayed superior pigment inhibitory activity, better hERG inhibitory properties and water solubility, and significantly sensitized MRSA strains to immune clearance in vitro.

Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer's Disease.

Through drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer's disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Importantly, 1w·Cit (citrate of 1w) could reverse the cognitive dysfunction of scopolamine-induced AD mice and exhibited an excellent effect on enhancing cAMP response element-binding protein (CREB) phosphorylation in vivo, a crucial factor in memory formation and synaptic plasticity.

Melting Point Distribution Analysis of Globally Approved and Discontinued Drugs: A Research for Improving the Chance of Success of Drug Design and Discovery.

The melting point (MP), an easily accessible physical parameter, has considerable potential for the judgment of drug-like properties. However, to the best of our knowledge, there are no useful guidelines for understanding the relationship between the MP and drug-like properties. To this end, we have constructed the largest MP database (experimental value) of globally approved drugs (3164 organic small-molecule drugs) and discontinued drugs (417 organic small-molecule drugs) and subsequently extracted six subdatabases from the whole approved database and two subdatabases from the discontinued database.