Discovery of Potent, Selective Stem Cell Factor Receptor/Platelet Derived Growth Factor Receptor Alpha (c-KIT/PDGFRα) Dual Inhibitor for the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors (GISTs)

Stem cell factor receptor (c-KIT) and platelet derived growth factor receptor alpha (PDGFRα) kinases play an important role in gastrointestinal stromal tumors (GISTs). Here, we have discovered an c-KIT/PDGFRα dual inhibitor, compound <b>31</b>, with single-digit nanomolar potency against c-KIT and PDGFRα. Compared to Imatinib (<b>1</b>), <b>31</b> showed better antiproliferative efficacy against various TEL-c-KIT/PDGFRα-BaF3 isogenic cells, including three <b>1</b>-resistant BaF3 cell lines, as well as against GIST-T1 and GIST-882 cell lines. Furthermore, compound <b>31</b> showed a good KinomeScan selectivity (468 kinases) (<i>S</i> score (1) = 0.01 at 1 μM concentration), good metabolic stability in liver microsomes, and no hERG inhibitory activity. It was worth noting that <b>31</b> inhibited GIST-T1 tumor growth (TGI = 81.5%) and even the BaF3-TEL-cKIT-T670I tumor progression (TGI = 41.9%, <b>1</b>-resistant GISTs) at a dosage of 100 mg/kg/day without exhibiting apparent toxicity

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 <b>2</b> has proven this method was feasible in AD mouse models. In this study, our work focused on exploring alternative novel tadalafil derivatives (<b>3a</b>–<b>s</b>). Among the 19 analogues, compound <b>3c</b> exhibited good selective dual-target AChE/PDE5 inhibition and good blood-brain barrier (BBB) permeability. Moreover, its citrate (<b>3c·Cit</b>) possessed improved water solubility and good effects against scopolamine-induced cognitive impairment with inhibition of cortical AChE activities and enhancement of cAMP response element-binding protein (CREB) phosphorylation <i>ex vivo</i>

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, <b>1p</b> and <b>1w</b> exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Importantly, <b>1w·Cit</b> (citrate of <b>1w</b>) 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. Moreover, the molecular docking simulations of <b>1w</b> with hAChE and hPDE5A confirmed that our design strategy was rational. In summary, our research provides a potential selective dual-target AChE/PDE5 inhibitor as a good candidate drug for the treatment of AD, and it could also be regarded as a small molecule probe to validate the novel AD therapeutic approach in vivo

Novel Staphyloxanthin Inhibitors with Improved Potency against Multidrug Resistant <i>Staphylococcus aureus</i>

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 <b>4a</b>. Derivative <b>47</b> displayed superior pigment inhibitory activity, better hERG inhibitory properties and water solubility, and significantly sensitized MRSA strains to immune clearance in vitro. Notably, <b>47</b> displayed excellent efficacy against pigmented <i>S. aureus</i> Newman, Mu50 (vancomycin-intermediate MRSA, VISA), and NRS271 (linezolid-resistant MRSA, LRSA) comparable to that of linezolid and vancomycin in vivo

Novel Inhibitors of Staphyloxanthin Virulence Factor in Comparison with Linezolid and Vancomycin versus Methicillin-Resistant, Linezolid-Resistant, and Vancomycin-Intermediate <i>Staphylococcus aureus</i> Infections in Vivo

Our previous work (Wang et al. J. Med. Chem. 2016, 59, 4831−4848) revealed that effective benzocycloalkane-derived staphyloxanthin inhibitors against methicillin-resistant <i>Staphylococcus aureus</i> (<i>S. aureus</i>) infections were accompanied by poor water solubility and high hERG inhibition and dosages (preadministration). In this study, 92 chroman and coumaran derivatives as novel inhibitors have been addressed for overcoming deficiencies above. Derivatives <b>69</b> and <b>105</b> displayed excellent pigment inhibitory activities and low hERG inhibition, along with improvement of solubility by salt type selection. The broad and significantly potent antibacterial spectra of <b>69</b> and <b>105</b> were displayed first with normal administration in the livers and hearts in mice against pigmented <i>S. aureus</i> Newman, Mu50 (vancomycin-intermediate <i>S. aureus</i>), and NRS271 (linezolid-resistant <i>S. aureus</i>), compared with linezolid and vancomycin. In summary, both <b>69</b> and <b>105</b> have the potential to be developed as good antibacterial candidates targeting virulence factors