Exploiting the Tolerant Region I of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility and Favorable Safety Profiles

Abstract

Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfonyl and sulfamide-substituted piperazine/piperidines were introduced into the right wing of DAPYs targeting the solvent-exposed tolerant region I. The anti-HIV-1 activities of 11c (EC 50(WT) = 0.0035 μM, EC 50(E138K) = 0.0075 μM) were the same as and 2-fold better than that of the lead etravirine against the wild-type and E138K mutant HIV-1, respectively, with a relative low cytotoxicity (CC 50 ≥ 173 μM). Further test showed a significant improvement in the water solubility of 11c. Besides, 11c displayed no significant inhibition on main cytochrome P450 enzymes and exhibited no acute/ subacute toxicities at doses of 2000 mg•kg −1 /50 mg•kg −1 in mice. Taken together, we consider that 11c is a promising lead for further structural optimization.

Structure‐based non‐nucleoside inhibitor design: Developing inhibitors that are effective against resistant mutants

“…Thus, there is a need to develop new NNRTIs, particularly new compounds that will be broadly effective against the known NNRTI‐resistant mutants. In an effort to seek improved solubility and bioavailability, others have reported the development of RPV analogs that have different modifications of the moieties that are linked to the pyrimidine core (Huang et al., 2019; Kang, Wang, et al, 2019; Kang, Zhang, et al, 2019; Liu et al., 2016). We have focused primarily on increasing the potency of RPV analogs against resistant strains of HIV.…”

A N-propionylsulfonamide prodrug of K-5a2 provided improved aqueous solubility and hERG inhibition

“…[22] Through predicting by ChemDraw, the alkalinity of HM-1 was decreased, which revealed that HM-1 may have lower hERG activity. Indeed, in vitro manual patch-clamp electrophysiology was used to evaluate the activity against the hERG potassium channel to estimate the potential risk for cardiotoxicity, [23] and the result veri ed our prediction exactly.…”

An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 Subunit

“…Our structural conservation analysis showed the compound 2 binding region on HIV-1 p51 to be conserved across multiple RTs (Figure 5 and Supplementary Data). Since viruses can develop cross-resistance to multiple drugs [28,37,38], and Y183 has yet emerged as a drug resistant mutated location, compound 2 serves as a potentially crucial scaffold for targeting drug-resistant HIV-1 variants, and with the conservation of the site across a wide range of RT families, also as a possible broad-spectrum antiviral RTI. By taking a holistic approach [39] in studying the whole structure of the target proteins and looking for common sites and how resistance develops, as demonstrated for HIV-1 Gag [40], HIV-1 Protease [37], and antibodies [41][42][43][44][45][46], the search for common druggable conserved sites across protein families can add to the success of developing broad-spectrum therapeutics.…”