Design, Synthesis, and Evaluation of Thiophene[3,2-d]pyrimidine Derivatives as HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Drug Resistance Profiles

Abstract

We designed and synthesized a series of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a piperidine-substituted thiophene[3,2-d]pyrimidine scaffold, employing a strategy of structure-based molecular hybridization and substituent decorating. Most of the synthesized compounds exhibited broad-spectrum activity with low (single-digit) nanomolar EC50 values toward a panel of wild-type (WT), single-mutant, and double-mutant HIV-1 strains. Compound 27 was the most potent; compared with ETV, its antiviral efficacy was 3-fold greater against WT, 5-7-fold greater against Y181C, Y188L, E138K, and F227L+V106A, and nearly equipotent against L100I and K103N, though somewhat weaker against K103N+Y181C. Importantly, 27 has lower cytotoxicity (CC50 > 227 μM) and a huge selectivity index (SI) value (ratio of CC50/EC50) of >159101. 27 also showed favorable, drug-like pharmacokinetic and safety properties in rats in vivo. Molecular docking studies and the structure-activity relationships provide important clues for further molecular elaboration.

Challenges and approaches in the discovery of human immunodeficiency virus type‐1 non‐nucleoside reverse transcriptase inhibitors

“…Using structure‐based scaffold hopping and molecular hybridization approaches, Kang et al have synthesized several piperidine‐substituted thiophene[3,2‐d]pyrimidine derivatives. Particularly, compound 88 was threefold more potent than ETV against the WT form, five to sevenfold more potent against Y181C, Y188L, E138K, and F227L + V106A and equipotent against L1001 and K103N(Figure ).…”

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.…”

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

“…Further investigation of the central core ring and the right wing to use tolerant regions I and II to obtain potent and highly selective DAPY derivatives against the common HIV‐1 mutant strains was performed by Liu and co‐workers. For this purpose, a number of piperidine‐linked thiophene [3,2‐ d ]pyrimidine derivatives were prepared using the molecular hybridization approach . Most of the obtained compounds showed excellent activity against the wild‐type HIV‐1 strain at an EC 50 value of less than 5 n m , similar to that of the reference NNRTI etravirine.…”