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

  • Bioorg Med Chem Lett. 2025 Dec 1:128:130345. doi: 10.1016/j.bmcl.2025.130345.
Theresa H Nguyen  1 ,  Omar Moukha-Chafiq  2 ,  Shuklendu Karyakarte  1 ,  Ana C Jimenez-Torres  3 ,  Ganesh Shrestha  1 ,  Sixue Zhang  1 ,  Jun Zhu  3 ,  Corinne E Augelli-Szafran  1
Affiliations
  • 1. Scientific Platforms Division, Southern Research, 2000 9(th) Avenue South, Birmingham, AL 35205, USA.
  • 2. Scientific Platforms Division, Southern Research, 2000 9(th) Avenue South, Birmingham, AL 35205, USA. Electronic address: [email protected].
  • 3. Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
PMID: 40712895 DOI: 10.1016/j.bmcl.2025.130345
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.

Keywords
Dopamine uptake, dopamine transporter (DAT), HIV-1 tat protein; HIV-1 associated neurocognitive disorders (HAND); Small molecule allosteric modulators.
Products