Structure-Based Optimization of Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Improved Potency against Resistance-Associated Variants

Abstract

This work follows on from our initial discovery of a series of piperidine-substituted thiophene[3,2-d]pyrimidine HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) ( J. Med. Chem. 2016 , 59 , 7991 - 8007 ). In the present study, we designed, synthesized, and biologically tested several series of new derivatives in order to investigate previously unexplored chemical space. Some of the synthesized compounds displayed single-digit nanomolar anti-HIV potencies against wild-type (WT) virus and a panel of NNRTI-resistant mutant viruses in MT-4 cells. Compound 25a was exceptionally potent against the whole viral panel, affording 3-4-fold enhancement of in vitro antiviral potency against WT, L100I, K103N, Y181C, Y188L, E138K, and K103N+Y181C and 10-fold enhancement against F227L+V106A relative to the reference drug etravirine (ETV) in the same cellular assay. The structure-activity relationships, pharmacokinetics, acute toxicity, and cardiotoxicity were also examined. Overall, the results indicate that 25a is a promising new drug candidate for treatment of HIV-1 infection.

Development of a practical synthesis of etravirine via a microwave-promoted amination

“…In the preliminary study, we conducted the reaction in an autoclave as the conventional synthesis [5] (Scheme 5). The amination reaction performed very well as the literature reported and the yield ranged from 82.7 to 83.6%.…”

“…However, the rapid emergence of drug-resistant HIV-1 strains limited their clinical use [1–4]. Etravirine, 2,4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile, a second-generation drug of the diarylpyrimidine-based NNRTIs, was approved in 2008 by the U.S. Federal Drug Administration (FDA) for use in HAART [5]. Etravirine is a well-tolerated NNRTI with higher genetic barrier for resistance and good safety profiles compared to the first-generation NNRTIs [6].…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…Compared with 6 , piperidine‐linked aminopyrimidine derivatives 7 and 8 possess broad potency against resistant mutant viruses (including the K103N/Y181C and Y188L mutants). Compared with ETV, the piperidine‐linked thiophene[3,2‐d]pyrimidines 9 and 10 were exceptionally active against the whole viral panel, including wild‐type (WT), L100I, K103N, E138K, Y181C, Y188L, F227L/V106A, and K103N/Y181C (Figure ) . Importantly, 9 has lower cytotoxicity (CC 50 > 227 μM) and a huge selectivity index (SI) value of >159101.…”

“…18 In an effort to more fully explore the structure-activity relationships (SARs) of the diarylpyrimidine (DAPY)-based NNRTIs (exemplified by 6, etravirine, ETV) and potentially attenuate the resistance of the existing mutants, a further investigation of the interactions of the DAPYs with the solvent-exposed region of RT resulted in the identification of piperidine-linked aminopyrimidine and thiophene [3,2-d]pyrimidine derivatives, which exhibited broad-spectrum activity with low (single-digit) nanomolar EC 50 values toward a panel of WT, single-mutant, and double-mutant HIV-1 strains. [19][20][21][22][23][24][25] Compared with 6, piperidine-linked aminopyrimidine derivatives 7 and 8 possess broad potency against…”

Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

“…Considering the obtained results, particularly the antiviral efficacy of the most potent compound 47 a , this class of compounds did not show considerable activity against the most common single‐mutant strain K103N and the most challenging variant strain RES056 in comparison with etravirine. Thus, with the aim of improving their potency against drug‐resistant strains K103N and RES056, a few series of 47 a analogues were prepared by focusing on refinement of the cyano group of the left wing and the piperidylamine moiety of the right wing …”