Identification of Dihydrofuro[3,4-d]pyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Promising Antiviral Activities and Desirable Physicochemical Properties

Abstract

To address drug resistance to HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel diarylpyrimidine (DAPY) derivatives targeting "tolerant region I" and "tolerant region II" of the NNRTIs binding pocket (NNIBP) were designed utilizing a structure-guided scaffold-hopping strategy. The dihydrofuro [3,4-d]pyrimidine derivatives 13c2 and 13c4 proved to be exceptionally potent against a wide range of HIV-1 strains carrying single NNRTI-resistant mutations (EC 50 = 0.9−8.4 nM), which were remarkably superior to that of etravirine (ETV). Meanwhile, both compounds exhibited comparable activities with ETV toward the virus with double mutations F227L+V106A and K103N+Y181C. Furthermore, the most active compound 13c2 showed favorable pharmacokinetic properties with an oral bioavailability of 30.96% and a half-life of 11.1 h, which suggested that 13c2 is worth further investigation as a novel NNRTI to circumvent drug resistance.

In silico Design of Novel HIV-1 NNRTIs Based on Combined Modeling Studies of Dihydrofuro[3,4-d]pyrimidines

“…A total of 52 DHPY derivatives were collected from the published literature (Kang et al, 2019) for performing the molecular modeling study. Their structures, EC 50 , and corresponding pEC 50 (− log EC 50 ) values were listed in Table 1.…”

“…However, compound K-5a2 did not display excellent activity against K103N+Y181C mutant HIV-1 strains (Kang et al, 2017;Yang et al, 2018). Further structural modification on K-5a2 and 25a using six alicyclic-fused pyrimidine rings led to a series of dihydrofuro[3,4-d]pyrimidine (DHPY) derivatives with potent anti-HIV activity (Table 1) (Kang et al, 2019).…”

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…”

“…Compared with ETV, the piperidinelinked thiophene[3,2-d]pyrimidines 9 and 10 were exceptionally active against the whole viral panel, including wildtype (WT), L100I, K103N, E138K, Y181C, Y188L, F227L/V106A, and K103N/Y181C ( Figure 4). [21][22][23][24][25] Importantly, 9 has lower cytotoxicity (CC 50 > 227 μM) and a huge selectivity index (SI) value of >159101. Moreover, 9 also displayed favorable PK and safety profiles in rats in vivo.…”