Improved Water Solubility Research Articles

A pH-responsive nanoplatform with aggregation-induced emission features for lipid droplet imaging in atherosclerosis

Hydrophobic lipid droplets (LDs)-specific fluorescent probes have shown great potential in bioimaging. However, their in vivo bioapplications are also limited by their strong hydrophobic nature. To address this issue, we prepared a novel tetraphenylethylene (TPE)-based fluorescent probe, namely, MeOTTI, and a pH-responsive polymeric micelle to establish a nanodiagnostic system for the imaging of LDs in atherosclerosis. MeOTTI demonstrated good LDs-specific imaging capability with good anti-photobleaching ability but poor water solubility. MeOTTI-encapsulated nanoparticles (MeOTTI-PMEA NPs) have shown improved water solubility and biocompatibility of MeOTTI. MeOTTI-PMEA NPs exhibited great stability at pH 7.4, while they showed good acid-responsive ability with accelerated MeOTTI release. Importantly, MeOTTI-PMEA NPs could efficiently light up the LDs in cells and in mice atherosclerosis plaques. The construction of LDs-specific probe-loaded nanodiagnostic system is expected to create enthusiasm for the development of new tools for bioimaging.

Enhancing Giardicidal Activity and Aqueous Solubility through the Development of "RetroABZ", a Regioisomer of Albendazole: In Vitro, In Vivo, and In Silico Studies.

Parasitic diseases, including giardiasis caused by Giardia lamblia (G. lamblia), present a considerable global health burden. The limited effectiveness and adverse effects of current treatment options underscore the necessity for novel therapeutic compounds. In this study, we employed a rational design strategy to synthesize retroalbendazole (RetroABZ), aiming to address the limitations associated with albendazole, a commonly used drug for giardiasis treatment. RetroABZ exhibited enhanced in vitro activity against G. lamblia trophozoites, demonstrating nanomolar potency (IC50 = 83 nM), outperforming albendazole (189 nM). Moreover, our in vivo murine model of giardiasis displayed a strong correlation, supporting the efficacy of RetroABZ, which exhibited an eleven-fold increase in potency compared to albendazole, with median effective dose (ED50) values of 5 µg/kg and 55 µg/kg, respectively. A notable finding was RetroABZ's significantly improved water solubility (245.74 µg/mL), representing a 23-fold increase compared to albendazole, thereby offering potential opportunities for developing derivatives that effectively target invasive parasites. The molecular docking study revealed that RetroABZ displays an interaction profile with tubulin similar to albendazole, forming hydrogen bonds with Glu198 and Cys236 of the β-tubulin. Additionally, molecular dynamics studies demonstrated that RetroABZ has a greater number of hydrophobic interactions with the binding site in the β-tubulin, due to the orientation of the propylthio substituent. Consequently, RetroABZ exhibited a higher affinity compared to albendazole. Overall, our findings underscore RetroABZ's potential as a promising therapeutic candidate not only for giardiasis but also for other parasitic diseases.

Performance and Solution Structures of Side-Chain-Bridged Oligo (Ethylene Glycol) Polymer Photocatalysts for Enhanced Hydrogen Evolution under Natural Light Illumination.

Converting solar energy into hydrogen energy using conjugated polymers (CP) is a promising solution to the energy crisis. Improving water solubility plays one of the critical factors in enhancing the hydrogen evolution rate (HER) of CP photocatalysts. In this study, a novel concept of incorporating hydrophilic side chains to connect the backbones of CPs to improve their HER is proposed. This concept is realized through the polymerization of carbazole units bridged with octane, ethylene glycol, and penta-(ethylene glycol) to form three new side-chain-braided (SCB) CPs: PCz2S-OCt, PCz2S-EG, and PCz2S-PEG. Verified through transient absorption spectra, the enhanced capability of PCz2S-PEG for ultrafast electron transfer and reduced recombination effects has been demonstrated. Small- and wide-angle X-ray scattering (SAXS/WAXS) analyses reveal that these three SCB-CPs form cross-linking networks with different mass fractal dimensions (f) in aqueous solution. With the lowest f value of 2.64 and improved water/polymer interfaces, PCz2S-PEG demonstrates the best HER, reaching up to 126.9µmolh-1 in pure water-based photocatalytic solution. Moreover, PCz2S-PEG exhibits comparable performance in seawater-based photocatalytic solution under natural sunlight. In situ SAXS analysis further reveals nucleation-dominated generation of hydrogen nanoclusters with a size of ≈1.5nm in the HER of PCz2S-PEG under light illumination.

Nanoparticle encapsulation using self-assembly abietic acid to improve oral bioavailability of curcumin

This research constructed composite nanoparticles (NPs) using abietic acid (AA) as a carrier for significantly enhancing the bioavailability of curcumin (CCM). CCM-loaded AA NPs were synthesized using a low-energy microemulsification method, and the obtained nanoparticles had a spherical morphology with an average diameter of 458.66 nm, a narrow size distribution and a negative surface charge of −19.13 mV. The encapsulation efficiency of CCM was 17.98 %, while its solubility was 20-fold that of free curcumin. FITR, UV, and MD revealed hydrogen bonds and hydrophobic forces between AA and CCM. Thein-vitrorelease profile showed sustainable release of CCM in simulated gastric and intestinal fluids up to 2 h at 37 °C. In cellular studies, CCM-loaded AA NPs with the same CCM concentration exhibited greater bioaccessibility and bioavailability than free CCM. These data suggested a possible utilization of AA NPs in improving water solubility, bioavailability and activity of lipophilic bioactive food factors.

Epoxy silane sulfobetaine block copolymers for simple, aqueous thromboresistant coating on ambulatory assist lung devices.

Developing an ambulatory assist lung (AAL) for patients who need continuous extracorporeal membrane oxygenation has been associated with several design objectives, including the design of compact components, optimization of gas transfer efficiency, and reduced thrombogenicity. In an effort to address thrombogenicity concerns with currently utilized component biomaterials, a low molecular weight water soluble siloxane-functionalized zwitterionic sulfobetaine (SB-Si) block copolymer was coated on a full-scale AAL device set via a one pot aqueous circulation coating. All device parts including hollow fiber bundle, housing, tubing and cannular were successfully coated with increasing atomic compositions of the SB block copolymer and the coated surfaces showed a significant reduction of platelet deposition while gas exchange performance was sustained. However, water solubility of the SB-Si was unstable, and the coating method, including oxygen plasma pretreatment on the surfaces were considered inconsistent with the objective of developing a simple aqueous coating. Addressing these weaknesses, SB block copolymers were synthesized bearing epoxy or epoxy-silane groups with improved water solubility (SB-EP & SB-EP-Si) and no requirement for surface pretreatment (SB-EP-Si). An SB-EP-Si triblock copolymer showed the most robust coating capacity and stability without prior pretreatment to represent a simple aqueous circulation coating on an assembled full-scale AAL device.

Biological evaluation of a phosphate ester prodrug of 10-methyl-aplog-1, a simplified analog of aplysiatoxin, as a possible latency-reversing agent for HIV reactivation.

10-Methyl-aplog-1 (10MA-1), a simplified analog of aplysiatoxin, exhibits a high binding affinity for protein kinase C (PKC) isozymes with minimal tumor-promoting and pro-inflammatory activities. A recent study suggests that 10MA-1 could reactivate latent human immunodeficiency virus (HIV) in vitro for HIV eradication strategy. However, further in vivo studies were abandoned by a dose limit caused by the minimal water solubility of 10MA-1. To overcome this problem, we synthesized a phosphate ester of 10MA-1, 18-O-phospho-10-methyl-aplog-1 (phos-10MA-1), to improve water solubility for in vivo studies. The solubility, PKC binding affinity, and biological activity of phos-10MA-1 were examined in vitro, and the biological activity was comparable with 10MA-1. The pharmacokinetic studies in vivo were also examined, which suggest that further optimization for improving metabolic stability is required in the future.

Development of pH-sensitive films based on buckwheat starch, critic acid and rose petal extract for active food packaging

The pH sensitive films were developed by casting method using buckwheat starch (BS, 5% dry basis) as a base material, citric acid (CA, 1–5% w/w of dry starch) as a crosslinker, and natural rose petals extract (RE, 5–15% v/v of the total solution) as a pH indicator. RE increased the thickness, moisture, elongation at break, UV–vis light barrier ability, and antioxidant properties of films. The interaction between anthocyanin and starch was confirmed by FTIR, which showed band shifting near 995 cm−1. At higher RE concentrations, the surface of the film became rough and uneven due to agglomeration of extract materials. In contrast, CA improved water solubility, tensile strength, and UV rays blocking by forming ester linkage between starch molecules. Increasing RE and CA reduced the crystallinity of films (from 37.32% to 18.56%), which improved flexibility. All RE-containing films changed their color from pinkish to greenish yellow as the pH increased from 5 to 9. The film containing 5% of CA and 6.36% of RE was found to be more desirable and could be used as smart packaging for monitoring food quality and safety.

Ultra-small magnetic Candida antarctica lipase B nanoreactors for enzyme synthesis of bixin-maltitol ester.

Bixin has desirable bioactivities but poor water solubility, which limits its practical applications. Enzymatic transesterification of methyl to alditol groups in bixin by Candida antarctica lipase B (CALB) improves bixin water solubility. Herein, magnetic CALB nanoreactors with diameter of 11.7nm and CALB layer thickness of 3.5nm were developed by covalently linking CALB onto silicon covered Fe3O4 nanoparticles. The CALB loading capacity in nanoreactors achieved 30%. The Michaelis constant (Km) and maximum reaction rate of magnetic CALB nanoreactors were 56.1mmol/L and 0.2mmol/(L·min). Magnetic CALB nanoreactors could circularly catalyze bixin-maltitol ester synthesis and keep catalytic efficiency of 62.6% after eight repetitive enzymatic reactions. Additionally, the optimal bixin-maltitol ester synthesis procedure was heating bixin-maltitol mixture at molar ratio of 1:7 in anhydrous 2-methyl-2-butanol-dimethylsulfoxide (8:2, v/v) at 50°C for 24h. Bixin-maltitol ester showed improved water solubility at pH 5.5 and 7.0.

Peptide-Targeted Photosensitisers: Synthesis and Applications in Photobiology

The conjugation of porphyrin derivatives to peptide ligands is a valuable strategy for enhancing their aqueous solubility and tissue selectivity in the photodynamic therapy (PDT) of cancer. To this end, bioorthogonal ligation (“click”) chemistries provide an efficient way to link porphyrins and other tetrapyrrole systems with complementary multifunctional peptides. We will describe some of our work in this area towards the generation of specific targeted conjugates between porphyrin and chlorin derivatives and tumour-homing or cell-penetrating peptide carriers [1, 2]. Linking otherwise hydrophobic photosensitisers to cationic cell-penetrating peptides (e.g. HIV Tat 48-57) provides amphiphilic derivatives with improved water solubility plus enhanced cellular uptake and predictable sub-cellular localisation. Such molecules are very suitable for use in the light-triggered delivery of macromolecular therapeutics by photochemical internalisation (PCI), which will be illustrated for the targeted delivery of the protein toxin, saporin [3].Peptide targeting strategies are also valuable for PDT with 5-aminolevulinic acid (ALA) [4]. In ALA-PDT, administered ALA is converted within cells via the heme biosynthetic pathway to protoporphyrin IX which may then be exploited as a photosensitiser. In this context, we will present some recent chemical and biological data on the application of peptide targeting for the enhanced delivery of multiple ALA units to specific cell types [5].

Cationic Carbon Monoxide-Releasing Polymers as Antimicrobial and Antibiofilm Agents by the Synergetic Activity.

Recent studies indicate that carbon monoxide-releasing molecules (CORMs), a class of organometallic compounds, exert antibacterial activities through the delivery of carbon monoxide (CO) molecules. We developed a new-class CO-delivery system by conjugating classical low-molecular-weight CORMs (i.e., [Ru(CO)3Cl2]2 and Mn(CO)5Br) onto a positively charged carrier, polyimidazolium (PIM), giving cationic CO-releasing polymers Ru@PIM and Mn@PIM, respectively. Compared with low-molecular-weight CORMs, our polymeric CO vehicles showed improved water solubility, reduced cytotoxicity, significantly extended CO-releasing duration, and enhanced antimicrobial ability against both planktonic and biofilm microorganisms. Ru@PIM and Mn@PIM inhibited the growth of a broad spectrum of free Gram-positive and Gram-negative bacteria as well as fungus with the lowest minimum inhibitory concentration (MIC) at 8 μg/mL. They were effective in preventing pathogenic Pseudomonas aeruginosa biofilm formation with biofilm reduction by more than 92% at 16 μg/mL and 99% at 32 μg/mL. They also demonstrated potent dispersal efficacy on recalcitrant well-established biofilms through a synergetic activity with a biofilm log10 reduction of 2.5-3.2 ≥ 64 μg/mL and nearly 2.0 at the concentration of as low as 16 μg/mL. This CO-releasing system may retain long-time antimicrobial ability after the complete release of CO molecules owing to the cationic structure. The novel CO-releasing polymers have great potential as antimicrobial and antibiofilm agents in biomedical applications.

The Homoleptic Curcumin-Copper Single Crystal (ML2): A Long Awaited Breakthrough in the Field of Curcumin Metal Complexes.

The first single crystal structure of the homoleptic copper (II) ML2 complex (M=Cu (II), L = curcumin) was obtained and its structure was elucidated by X-ray diffraction showing a square planar geometry, also confirmed by EPR. The supramolecular arrangement is supported by C-H···O interactions and the solvent (MeOH) plays an important role in stabilizing the crystal packing Crystallinity was additionally assessed by XRD patterns. The log P value of the complex (2.3 ± 0.15) was determined showing the improvement in water solubility. The cytotoxic activity of the complex against six cancer cell lines substantially surpasses that of curcumin itself, and it is particularly selective against leukemia (K562) and human glioblastoma (U251) cell lines, with similar antioxidant activity to BHT. This constitutes the first crystal structure of pristine curcumin complexed with a metal ion.

Systematic Engineering of Saccharomyces cerevisiae Chassis for Efficient Flavonoid-7-O-Disaccharide Biosynthesis.

Flavonoids are an essential class of secondary metabolites found in plants and possess various nutritional, medicinal, and agricultural properties. However, the poor water solubility of flavonoid aglycones limits their potential applications. To overcome this issue, glycosylation is a promising approach for improving water solubility and bioavailability. In this study, we constructed a flavonoid-7-O-disaccharide biosynthetic pathway with flavonoid aglycones as substrates in Saccharomyces cerevisiae. Subsequently, through metabolic engineering and promoter strategies, we constructed a UDP-rhamnose regeneration system and optimized the UDP-glucose (UDPG) synthetic pathway. The optimized strain produced up to 131.3 mg/L eriocitrin. After this, the chassis cells were applied to other flavonoids, with substrates such as (2S)-naringenin, (2S)-hesperetin, diosmetin, and (2S)-eriodictyol, which resulted in the synthesis of 179.9 mg/L naringin, 276.6 mg/L hesperidin, 249.0 mg/L neohesperidin, 30.4 mg/L diosmin, and 100.7 mg/L neoeriocitrin. To the best of our knowledge, this is the first report on the biosynthesis of flavonoid-7-O-disaccharide.

A mannitol-modified emodin nano-drug restores the intestinal barrier function and alleviates inflammation in a mouse model of DSS-induced ulcerative colitis

BackgroundUlcerative colitis (UC) is an inflammatory disease of the colon that is characterized by mucosal ulcers. Given its increasing prevalence worldwide, it is imperative to develop safe and effective drugs for treating UC. Emodin, a natural anthraquinone derivative present in various medicinal herbs, has demonstrated therapeutic effects against UC. However, low bioavailability due to poor water solubility limits its clinical applications.MethodsEmodin-borate nanoparticles (EmB) were synthesized to improve drug solubility, and they modified with oligomeric mannitol into microgels (EmB-MO) for targeted delivery to intestinal macrophages that express mannose receptors. UC was induced in a mouse model using dextran sulfate sodium (DSS), and different drug formulations were administered to the mice via drinking water. The levels of inflammation-related factors in the colon tissues and fecal matter were measured using enzyme-linked immunosorbent assay. Intestinal permeability was evaluated using fluorescein isothiocyanate dextran. HE staining, in vivo imaging, real-time PCR, and western blotting were performed to assess intestinal barrier dysfunction.ResultsBoth EmB and EmB-MO markedly alleviated the symptoms of UC, including body weight loss, stool inconsistency, and bloody stools and restored the levels of pro- and anti-inflammatory cytokines. However, the therapeutic effects of EmB-MO on the macroscopic and immunological indices were stronger than those of EmB and similar to those of 5-aminosalicylic acid. Furthermore, EmB-MO selectively accumulated in the inflamed colon epithelium and restored the levels of the gut barrier proteins such as ZO-1 and Occludin.ConclusionsEmB-MO encapsulation significantly improved water solubility, which translated to greater therapeutic effects on the immune balance and gut barrier function in mice with DSS-induced UC. Our findings provide novel insights into developing emodin-derived drugs for the management of UC.

Smart Targeted Delivery Systems for Enhancing Antitumor Therapy of Active Ingredients in Traditional Chinese Medicine.

As a therapeutic tool inherited for thousands of years, traditional Chinese medicine (TCM) exhibits superiority in tumor therapy. The antitumor active components of TCM not only have multi-target treatment modes but can also synergistically interfere with tumor growth compared to traditional chemotherapeutics. However, most antitumor active components of TCM have the characteristics of poor solubility, high toxicity, and side effects, which are often limited in clinical application. In recent years, delivering the antitumor active components of TCM by nanosystems has been a promising field. The advantages of nano-delivery systems include improved water solubility, targeting efficiency, enhanced stability in vivo, and controlled release drugs, which can achieve higher drug-delivery efficiency and bioavailability. According to the method of drug loading on nanocarriers, nano-delivery systems can be categorized into two types, including physically encapsulated nanoplatforms and chemically coupled drug-delivery platforms. In this review, two nano-delivery approaches are considered, namely physical encapsulation and chemical coupling, both commonly used to deliver antitumor active components of TCM, and we summarized the advantages and limitations of different types of nano-delivery systems. Meanwhile, the clinical applications and potential toxicity of nano-delivery systems and the future development and challenges of these nano-delivery systems are also discussed, aiming to lay the foundation for the development and practical application of nano-delivery systems of TCM in clinical settings.

Highly Water-Dispersed and Stable Deinoxanthin Nanocapsule for Effective Antioxidant and Anti-Inflammatory Activity.

Deinoxanthin (DX), a carotenoid, has excellent antioxidant and anti-inflammatory properties. However, owing to its lipophilicity, it is unfavorably dispersed in water and has low stability, limiting its application in cosmetics, food, and pharmaceuticals. Therefore, it is necessary to study nanoparticles to increase the loading capacity and stability of DX. In this study, DX-loaded nanocapsules (DX@NCs) were prepared by nanoprecipitation by loading DX into nanocapsules. The size, polydispersity index, surface charge, and morphology of DX@NCs were confirmed through dynamic light scattering and transmission electron microscopy. The loading content and loading efficiency of DX in DX@NCs were analyzed using high-performance liquid chromatography. The antioxidant activity of DX@NCs was evaluated by DPPH assay and in vitro ROS. The biocompatibility of DX@NCs was evaluated using an in vitro MTT assay. In vitro NO analysis was performed to determine the effective anti-inflammatory efficacy of DX@NCs. DX@NCs exhibited increased stability and antioxidant efficacy owing to the improved water solubility of DX. The in situ and in vitro antioxidant activity of DX@NCs was higher than that of unloaded DX. In addition, it showed a strong anti-inflammatory effect by regulating the NO level in an in vitro cell model. This study presents a nanocarrier to improve the water-soluble dispersion and stability of DX. These results demonstrate that DX@NC is a carrier with excellent stability and has a high potential for use in cosmetic and pharmaceutical applications owing to its antioxidant and anti-inflammatory effects.

Triazinium Ligation: Bioorthogonal Reaction of N1‐Alkyl 1,2,4‐Triazinium Salts**

AbstractThe development of reagents that can selectively react in complex biological media is an important challenge. Here we show that N1‐alkylation of 1,2,4‐triazines yields the corresponding triazinium salts, which are three orders of magnitude more reactive in reactions with strained alkynes than the parent 1,2,4‐triazines. This powerful bioorthogonal ligation enables efficient modification of peptides and proteins. The positively charged N1‐alkyl triazinium salts exhibit favorable cell permeability, which makes them superior for intracellular fluorescent labeling applications when compared to analogous 1,2,4,5‐tetrazines. Due to their high reactivity, stability, synthetic accessibility and improved water solubility, the new ionic heterodienes represent a valuable addition to the repertoire of existing modern bioorthogonal reagents.

Triazinium Ligation: Bioorthogonal Reaction of N1-Alkyl 1,2,4-Triazinium Salts.

The development of reagents that can selectively react in complex biological media is an important challenge. Here we show that N1-alkylation of 1,2,4-triazines yields the corresponding triazinium salts, which are three orders of magnitude more reactive in reactions with strained alkynes than the parent 1,2,4-triazines. This powerful bioorthogonal ligation enables efficient modification of peptides and proteins. The positively charged N1-alkyl triazinium salts exhibit favorable cell permeability, which makes them superior for intracellular fluorescent labeling applications when compared to analogous 1,2,4,5-tetrazines. Due to their high reactivity, stability, synthetic accessibility and improved water solubility, the new ionic heterodienes represent a valuable addition to the repertoire of existing modern bioorthogonal reagents.

Synthesis of novobiocin derivatives and evaluation of their antigonococcal activity and pharmacokinetics

Gonorrhea has become a serious problem because the number of infected people is increasing and the multi-drug resistance of the causative bacteria, Neisseria gonorrhoeae, is progressing. To develop novel drugs against resistant N. gonorrhoeae, we focused on the antibiotic novobiocin (1). This natural product has a different mechanism of action from existing drugs for gonorrhea, which may make it effective against resistant strains. Actually, it was applied to resistant N. gonorrhoeae, and moderate antibacterial activity was confirmed. Based on this result, we investigated the development of an antigonococcal drug with 1 as the lead compound. The pharmacophore is thought to be the noviose sugar moiety, especially around the 3′-position, so we derivatized this part in order to improve antibacterial activity. As a result, we found that 5 with an methylpyrrole ester structure have a very potent antibacterial activity. This derivative also showed excellent antigonococcal activity against resistant strains in vitro, however it has poor water solubility and pharmacokinetics because it is the acidic lipid-soluble compound. Therefore, we considered introduction of a basic substituent into the molecule would result in an amphoteric compound with improved water solubility, and we investigated further derivatization. As a result of synthesizing various derivatives, we found 47 containing imidazole with strong antigonococcal activity and greatly improved water solubility. This derivative has also improved metabolism and blood concentration in vivo, and is expected to be orally absorbed. Based on these results, we believe that 47 is a very promising anti-gonococcal lead compound and has great potential for further development.

Development of o-aminobenzamide salt derivatives for improving water solubility and anti-undifferentiated gastric cancer.

Background: Gastric cancer is one of the cancers with wide incidence, difficult treatment and high mortality in the world, especially in Asia and Africa. In our previous work, a novel o-aminobenzamide analogue F8 was identified as an early preclinical candidate for treatment of undifferentiated gastric cancer (IC50 of 0.26μM for HGC-27). However, the poor water solubility of compound F8 prevents its further progress in preclinical studies. Aim: To improve the water solubility and drug-likeness of F8 via salt formation. Method: Different acids and F8 were reacted to obtain different salt forms. Physicochemical property screening, pharmacokinetic property research, and antitumor biological activity evaluation in vitro and in vivo were used to obtain the optimal salt form with the best druggability. Results: our continuous efforts have finally confirmed F8·2HCl as the optimal salt form with maintained in vitro antitumor activity, improved water solubility and pharmacokinetic properties. Importantly, the F8·2HCl displayed superior in vivo antitumor efficacy (TGI of 70.1% in 75mg/kg) in HGC-27 xenograft model. The further immunohistochemical analysis revealed that F8·2HCl exerts an antitumor effect through the regulation of cell cycle-related protein (CDK2 and p21), apoptosis-related protein Cleaved Caspase-3, proliferation marker Ki67, and cell adhesion molecule E-cadherin. In addition, F8·2HCl showed acceptable safety in the in vivo acute toxicity assay. Conclusion: Salting is an effective means to improve the drug-like properties of compound F8, and F8·2HCl can serve as a promising therapeutic agent against undifferentiated gastric cancer.

Discovery of novel diarypyrimidine derivatives bearing six-membered non-aromatic heterocycles as potent HIV-1 NNRTIs with improved anti-resistance and drug-like profiles

Taking our previously reported HIV-1 NNRTIs BH-11c and XJ-10c as lead compounds, series of novel diarypyrimidine derivatives bearing six-membered non-aromatic heterocycles were designed to improve anti-resistance and drug-like profiles. According to the three rounds of in vitro antiviral activity screening, compound 12g was the most active inhibitor against wild-type and five prevalent NNRTI-resistant HIV-1 strains with EC50 values ranging from 0.024 to 0.0010 μM. This is obviously better than the lead compound BH-11c and the approved drug ETR. Detailed structure-activity relationship was investigated to provide valuable guidance for further optimization. The MD simulation study indicated that 12g could form additional interactions with residues around the binding site in HIV-1 RT, which provided reasonable explanations for its improved anti-resistance profile compared to ETR. Furthermore, 12g showed significant improvement in water solubility and other drug-like properties compared to ETR. The CYP enzymatic inhibitory assay indicated that 12g was unlikely to induce CYP-mediated drug-drug interactions. 12g pharmacokinetics parameters were investigated and it displayed a long half-life of 6.59 h in vivo. The properties of compound 12g make it a promising lead compound for the development of new generation of antiretroviral drugs.