Synthesis and evaluation of novel substituted N-(2-phenylbutyl)-5,6,7,8-tetrahydro-quinazolin-4-amines as allosteric modulators of HIV-DAT-tat interaction

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-23 DOI:10.1016/j.bmcl.2025.130345

Theresa H. Nguyen , Omar Moukha-Chafiq , Shuklendu Karyakarte , Ana C. Jimenez-Torres , Ganesh Shrestha , Sixue Zhang , Jun Zhu , Corinne E. Augelli-Szafran

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Abstract

Allosteric modulation of interaction between Dopamine Transporter (DAT) and HIV-1 transactivator of transcription (Tat) by small molecules suggests a potential therapeutic intervention for HIV-infected patients with concurrent cocaine abuse. We have previously reported in vitro and in vivo studies on a novel allosteric modulator, SRI-32743, which was shown to attenuate Tat-induced inhibition of [³H]DA uptake and decrease the cocaine-mediated dissociation of [³H]WIN35,428 binding in CHO-K1 cells expressing hDAT. Herein we report our initial structure-activity relationship (SAR) studies on SRI-32743 with the goal of identifying more potent analogs with improved absorption, distribution, metabolism, and excretion (ADME) properties, that can evolve into a pre-clinical candidate against HIV-1 associated neurocognitive disorders (HAND). Our investigation led to the discovery of a novel N-(2-phenylbutyl)-5,6,7,8-tetrahydroquinazolin-4-amine 4e (SRI-45949), which exhibited comparable inhibitory potency and improved solubility as compared to SRI-32743.

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新型取代N-（2-苯基丁基）-5,6,7,8-四氢喹唑啉-4胺作为HIV-DAT-tat相互作用变构调节剂的合成与评价

小分子对多巴胺转运蛋白（DAT）和HIV-1转录反激活因子（Tat）之间相互作用的变构调节提示了对并发可卡因滥用的hiv感染患者的潜在治疗干预。我们之前报道了一种新型变构调节剂SRI-32743的体外和体内研究，该调节剂被证明可以减弱tat诱导的[3H]DA摄取抑制，并减少表达hDAT的CHO-K1细胞中可卡因介导的[3H]WIN35,428结合的解离。在此，我们报告了我们对SRI-32743的初步构效关系（SAR）研究，目的是鉴定出具有改善吸收、分布、代谢和排泄（ADME）特性的更有效的类似物，这些类似物可以演变成治疗HIV-1相关神经认知障碍（HAND）的临床前候选药物。我们的研究发现了一种新的N-（2-苯基丁基）-5,6,7,8-四氢喹唑啉-4-胺4e (SRI-45949)，与SRI-32743相比，它具有相当的抑制效力和更好的溶解度。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.