Physicochemical property-driven optimization of diarylaniline compounds as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

Using physicochemical property-driven optimization, twelve new diarylaniline compounds (DAANs) (7a–h, 11a–b and 12a–b) were designed and synthesized. Among them, compounds 12a–b not only showed high potency (EC50 0.96–4.92 nM) against both wild-type and drug-resistant viral strains with the lowest fold change (FC 0.91 and 5.13), but also displayed acceptable drug-like properties based on aqueous solubility and lipophilicity (LE > 0.3, LLE > 5, LELP < 10). The correlations between potency and physicochemical properties of these DAAN analogues are also described. Compounds 12a–b merit further development as potent clinical trial candidates against AIDS

Optimization of 2,4-diarylanilines as non-nucleoside HIV-1 reverse transcriptase inhibitors

The current optimization of 2,4-diarylaniline analogs (DAANs) on the central phenyl ring provided a series of new active DAAN derivatives 9a–9e, indicating an accessible modification approach that could improve anti-HIV potency against wild-type and resistant strains, aqueous solubility, and metabolic stability. A new compound 9e not only exhibited extremely high potency against wild-type virus (EC50 0.53 nM) and several resistant viral strains (EC50 0.36 – 3.9 nM), but also showed desirable aqueous solubility and metabolic stability, which were comparable or better than those of the anti-HIV-1 drug TMC278 (2). Thus, new compound 9e might be a potential drug candidate for further development of novel next-generation NNRTIs

Discovery of diarylpyridine derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

Two series (4 and 5) of diarylpyridine derivatives were designed, synthesized, and evaluated for anti-HIV-1 activity. The most promising compound, 5e, inhibited HIV-1 IIIB, NL4-3, and RTMDR1 with low nanomolar EC50 values and selectivity indexes of >10,000. The results of this study indicate that diarylpyridine can be used as a novel scaffold to derive a new class of potent NNRTIs, active against both wild-type and drug resistant HIV-1 strains

Design, Synthesis, and Preclinical Evaluations of Novel 4-Substituted 1,5-Diarylanilines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug Candidates

Twenty-one new 4-substituted diarylaniline compounds (DAANs) (Scheme 2, series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to sub-nanomolar EC50 values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC50 values at the sub-nanomolar level (0.29–0.87 nM), and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Drug-like physicochemical property assessments revealed that the most active DAANs (EC50 1–90 μg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (2). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates

Design, Synthesis, and Evaluation of Diarylpyridines and Diarylanilines as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

Based on the structures and activities of our previously identified non-nucleoside reverse transcriptase inhibitors (NNRTIs), we designed and synthesized two sets of derivatives, diarylpyridines (A) and diarylanilines (B), and tested their anti-HIV-1 activity against infection by HIV-1 NL4-3 and IIIB in TZM-bl and MT-2 cells, respectively. The results showed that most compounds exhibited potent anti-HIV-1 activity with low nanomolar EC50 values, and some of them, such as 13m, 14c, and 14e, displayed high potency with subnanomolar EC50 values, which were more potent than etravirine (TMC125, 1) in the same assays. Notably, these compounds were also highly effective against infection by multi-RTI-resistant strains, suggesting a high potential to further develop these compounds as a novel class of NNRTIs with improved antiviral efficacy and resistance profile

Diarylaniline Derivatives as a Distinct Class of HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

By using structure-based drug design and isosteric replacement, diarylaniline and 1,5-diarylbenzene-1,2-diamine derivatives were synthesized and evaluated against wild type HIV-1 and drug-resistant viral strains, resulting in the discovery of diarylaniline derivatives as a distinct class of next-generation HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) agents. The most promising compound 37 showed significant EC50 values of 0.003-0.032 μM against HIV-1 wild-type strains and of 0.005-0.604 μM against several drug-resistant strains. Current results also revealed important structure-activity relationship (SAR) conclusions for diarylanilines and strongly support our hypothesis that an NH2 group on the central benzene ring ortho to the aniline moiety is crucial for interaction with K101 of the NNRTI binding site in HIV-1 RT, likely by forming H-bonds with K101. Furthermore, molecular modeling studies with molecular mechanism/general born surface area (MM/GBSA) technology demonstrated the rationality of our hypothesis

Optimization of the Antiviral Potency and Lipophilicity of Halogenated 2,6-Diarylpyridinamines as a Novel Class of HIV-1 NNRTIS

Nineteen new halogenated diarylpyridinamine (DAPA) analogues (6a-n and 8a-e) modified on the phenoxy C-ring were synthesized and evaluated for anti-HIV activity and certain drug-like properties. Ten compounds showed high anti-HIV activity (EC50 0.3, LLE >5, LELP <10). With balanced potency and drug-like properties, 8c merits further development as an anti-HIV drug candidate

Optimization of N-aryl-6-methoxy-1,2,3,4-tetrahydroquinolines as tubulin polymerization inhibitors

Thirteen new -aryl 1,2,3,4-tetrahydroquinoline compounds (–, –, and –) were synthesized and evaluated for antitumor activity and drug-like properties. Compound exhibited high inhibitory potency with low nanomolar GI values of 16–20 nM in cellular assays, including excellent activity against the P-glycoprotein overexpressing cell line KBvin. Compound inhibited colchicine binding to tubulin and tubulin assembly with an IC value of 0.85 μM, superior to the reference compound CA4 (1.2 μM) in the same assay. In addition, also exhibited highly improved water solubility (75 μg/mL) and a suitable log value (3.43) at pH 7.4. With a good balance between antitumor potency and drug-like properties, compound could be a new potential drug candidate for further development. Current results on SAR studies and molecular modeling provided more insight about this class of compounds as tubulin polymerization inhibitors targeting the colchicine site

A compendium of genetic regulatory effects across pig tissues

The Farm Animal Genotype-Tissue Expression (FarmGTEx) project has been established to develop a public resource of genetic regulatory variants in livestock, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biological discovery and exploitation in animal breeding and human biomedicine. Here we show results from the pilot phase of PigGTEx by processing 5,457 RNA-sequencing and 1,602 whole-genome sequencing samples passing quality control from pigs. We build a pig genotype imputation panel and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We evaluate tissue specificity of regulatory effects and elucidate molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying 207 pig complex phenotypes and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, supporting the importance of pigs as a human biomedical model.</p

Rough Surface Enhanced Interfacial Synthesis of Core‐Shell Magnetic Fluorescent Microspheres for Enhanced Latent Fingerprint Visualization

Abstract Developing latent fingerprints is extremely significant for personal identification and criminal investigation. Sub‐micrometer core‐shell structured magnetic fluorescent composite which combines the merits of noncontact magnetic responsiveness and strong fluorescence emission is highly desired for the visualization of latent fingerprint on various substrates with high resolutions. However, it remains a great challenge to synthesize uniform magnetic fluorescent composites with well‐defined structure and functionalities due to the uncontrollable heterogeneous growth. Herein, a urea‐assisted rough interface precipitation method is proposed to controllably synthesize uniform core‐shell structured magnetic fluorescent composite microspheres (Fe3O4@mesoSiO2@Y2O3:Eu3+). The composite microspheres with magnetic core and mesoporous silica shell (Fe3O4@mesoSiO2) possess huge guest‐host interface, numerous nucleation sites, and rough surface morphology, facilitating the efficient adsorption of Y3+/Eu3+ ions, and further controllable interface deposition of metal (Y, Eu) hydroxides induced by slow release of OH− and CO32− anions via the in‐solution decomposition of urea. After subsequent thermal annealing, the obtained Fe3O4@mesoSiO2@Y2O3:Eu3+ microspheres possess high magnetization for convenient magnetic manipulation, strong fluorescence intensity and negligible quenching effect, enabling a superior performance in latent fingerprint visualization with high contrast and resolution on various substrates