2. Academic Validation
  3. 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

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

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: omoukha-chafiq@southernresearch.org.
  • 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.

Figures
Products