The global prevalence of acquired immunodeficiency syndrome (AIDS) has posed a significant threat to human over the past few decades [1], [2]. The reverse transcriptase (RT), a crucial tool involved in the reversal transcription process of HIV-1 virus life cycle from RNA to double-stranded DNA, has long been recognized as one of the primary targets for the development of anti-AIDS drugs [3], [4], [5]. The allosteric binding site of the RT enzyme is targeted by non-nucleoside reverse transcriptase inhibitors (NNRTIs), which induce structural changes and hinder the entry of nucleotides into the catalytic site, thereby impeding HIV DNA synthesis [6], [7], [8]. Currently, several NNRTIs have been granted marketing approval, encompassing the first-generation agents Nevirapine (NVP), Delavirdine (DLV), and Efavirenz (EFV); the second-generation drugs Etravirine (ETR), Rilpivirine (RPV), and Doravirine (DOR); as well as the recently approved medications Elsulfavirine (ESV) and Ainuovirine (ANV) [9], [10], [11], [12], [13]. The widespread use of these clinical drugs, however, has brought to light their inherent limitations including the rapid emergence of drug resistance, high cytotoxicity, poor water solubility, unsatisfactory pharmacokinetic properties and other toxic side effects [14], [15], [16], [17].

In recent years, substantial endeavors have been undertaken to promote the development of innovative NNRTIs [15], [18], [19], [20]. Among these series, diarylbenzopyrimidines (DABPs) were developed using molecular hybridization and fragment-based drug design strategies [21], [22]. The findings from the conducted studies indicated that the representative compound 1 demonstrated moderate activity against both wild-type (WT) HIV-1 and mutant strains, exhibiting comparable selectivity index to ETR (SI > 1099) and RPV (SI = 3490) [21]. The molecular docking studies revealed that the left-wing group of compound 1 occupied the hydrophobic region of the non-nucleoside reverse transcriptase inhibitor binding pocket, where the phenyl ring formed two π-π interactions with W229. The interaction between the left phenyl ring and Y181/Y188, however, was impeded, while the sulfonyl group lacks hydrogen bond donors, thereby preventing it from forming hydrogen bonds with K101.

The goal of our present research is to enhance the effectiveness, selectivity, and solubility of compound 1 by employing a structure-based drug design strategy. The cyanovinyl (CV) group, a structural feature present in compound 1, may potentially act as a “Michael acceptor” and lead to covalent modification of proteins, nucleic acids, or other biological entities (Fig. 1). The biphenyl fragment has been previously incorporated into the left wing of diarylpyrimidines as a substitute group for CV, aiming to enhance π–π and hydrophobic interactions with surrounding residues of wild-type HIV-1 RT [23], [24]. In addition, 4-aminopiperidine moiety was identified as advantageous in enhancing resistance and safety of inhibitors [25], [26], [27], [28]. The simultaneous integration of both the biphenyl fragment and 4-aminopyridine moiety into compound 1 afforded the target compound 7y. The docking study conducted using Schrödinger Maestro 11.4 in Fig. 1B–D revealed that the newly designed ligand was well positioned within the binding pocket, exhibiting a similar binding orientation to the parent compound 1 in the wild-type HIV-1 RT, thus confirming the feasibility of our design strategy. Therefore, this study described the synthesis of a series of novel biphenyl-quinazoline derivatives, accompanied by an assessment of their anti-HIV-1 activity and cytotoxicity.