Linker Moiety Research Articles

1,2,3-Triazoles as Biomimetics in Peptide Science.

Natural peptides are an important class of chemical mediators, essential for most vital processes. What limits the potential of the use of peptides as drugs is their low bioavailability and enzymatic degradation in vivo. To overcome this limitation, the development of new molecules mimicking peptides is of great importance for the development of new biologically active molecules. Therefore, replacing the amide bond in a peptide with a heterocyclic bioisostere, such as the 1,2,3-triazole ring, can be considered an effective solution for the synthesis of biologically relevant peptidomimetics. These 1,2,3-triazoles may have an interesting biological activity, because they behave as rigid link units, which can mimic the electronic properties of amide bonds and show bioisosteric effects. Additionally, triazole can be used as a linker moiety to link peptides to other functional groups.

Investigation of morphology, crystallinity, thermal stability, piezoelectricity and conductivity of PVDF nanocomposites reinforced with epoxy functionalized MWCNTs

In order to improve the dispersion state of multi-walled carbon nanotubes (MWCNTs) and to get a synergistic effect when incorporated in polyvinylidene flouride (PVDF) matrix, multi-walled carbon nanotubes (MWCNTs) were oxidized and then grafted with di-glycidyl ether of bisphenol-A (DGEBA) by a linker moiety, hexamethylene diamine (HMD). Modified MWCNTs (HD-MWCNTs) with various concentrations of 1.0 wt% to 10 wt% were incorporated in polyvinylidene fluoride (PVDF) matrix for the fabrication of polymeric nanocomposites (PVDF/HD-MWCNTs). Compared to pristine MWCNTs (P-MWCNTs), the structural and thermal analysis of both modified MWCNTs showed a well crystalline structure with a uniform tubular morphology as well as uniform and improved dispersion was achieved in their nanocomposites with PVDF. Enhanced dispersion is attributed to a strong interfacial interaction of the modified MWCNTs with polymer chains of PVDF. Therefore, by thermal analysis of PVDF/HD-MWCNTs nanocomposites both melting temperature (Tm) and temperature of crystallization (Tc) have revealed the uniform distribution of nanotubes and enhancement of heterogeneous nucleating effect leading to formation of β-phase which is in complete agreement with SEM, FTIR, XRD, TGA and d33 value. Piezoelectric and electrical conductivity values measured for PVDF/HD-MWCNTs nanocomposites were observed to rise with increase in concentration of HD-MWCNTs up to 5 wt% where the percolation threshold (fc) is attained. PVDF/HD-MWCNTs nanocomposite with highest electrical conductivity of 1.13 x 10−3 Scm−1 at filler loading of 5 wt% was successfully achieved. These simultaneous improvement in properties anticipate that PVDF/HD-MWCNTs nanocomposites can be useful for variety of energy applications.

Pyrido[3,4‐d]pyrimidine as an Acceptor of Thermally Activated Delayed Fluorescent Emitters: Time‐dependent Density Functional Theory Study

Pyrido[3,4‐d]pyrimidine (PyPm) was designed as a new acceptor of thermally activated delayed fluorescent (TADF) emitters and the potential of the new acceptor moiety for TADF properties was investigated. Time‐dependent density functional theory calculation was performed to estimate TADF characteristics by comparing five isomers of PyPm‐based TADF emitters. Geometries of the emitters were affected by the presence of hydrogen bonding depending on the substitution position of the phenyl linker in the donor‐phenyl linker‐acceptor type backbone structure, which also influenced the molecular orbital distributions. The nature of the triplet excited state was also dependent on the substitution position of the phenyl linker and donor moiety in the molecular structure, and the substitution at 5 position of the PyPm provided small singlet‐triplet energy gap and hybridized local and charge transfer triplet excited state for efficient reverse intersystem crossing. From the computational calculation results, it can be expected that PyPm would effectively work as an acceptor of TADF emitters.

Appraisal of pyrrole as connecting unit in hydroxamic acid based histone deacetylase inhibitors: Synthesis, anticancer evaluation and molecular docking studies

Pyrrole is a biologically active scaffold, which itself possess noticeable anticancer activity against several types of cancer specially leukemia, lymphoma, and myelofibrosis. SAHA and its synthetic analogs has demonstrated potent antitumor activity against numerous human cancer lines and different classes of HDACs. The HDAC inhibitor possessing pyrrole as linker moiety has been developed for anticancer property. The objective of present studies was to incorporate pyrrole as connecting unit in hydroxamic acid based HDAC inhibitors for their anticancer evaluation and molecular docking studies. A series of novel 4-substituted methyl 6-(3-acetyl-2-methyl-1H-pyrrol-1-yl)hexanoate [3(a-z)] and 4-substituted 6-(3-acetyl-2-methyl-1H-pyrrol-1-yl)-N-hydroxyhexanamide [4(a-z)] were synthesized. These analogs were evaluated for their anticancer activity using in-vitro method against leukemia (K-562), lung (A-549), breast (MCF-7), and cervical (HeLa) human cancer cell lines using Sulforhodamine B (SRB) assay method, HDAC1 and HDAC6 inhibitory assay and binding mode analysis using molecular docking studies. The in-vitro studies of 3(a-z) indicated that substitution with electron donating groups produces active or moderately active compounds. Interestingly, p-nitro-substituted molecule produced a most active derivative in the series. The in-vitro anticancer study of 4(a-z) indicated that the unsubstituted phenyl derivative, 6-(3-acetyl-2-methyl-4-phenyl-1H-pyrrol-1-yl)-N-hydroxy-hexanamide (4a) have moderate antitumor activity against K-562 human leukemia cell line. Substitution at 4-phenyl ring with weak and moderate electron withdrawing groups, such as fluoro, chloro, and bromo potentiated the cytotoxic activity. The 4(a-z)] were docked against different HDAC proteins to determine the exact binding mode and orientation. These synthetic analogs have similar binding mode as SAHA on the active pocket. The pyrrole based novel SAHA analogs 3(a-z) and 4(a-z) displayed promising anticancer activity. These studies can be further employed for the design and development of novel SAHA analogs with promising anticancer activity.

Targeting Guanine Quadruplexes with Luminescent Platinum(II) Complexes Bearing a Pendant Nucleobase.

Guanine quadruplexes are tetra-stranded nucleic acid structures currently raising significant interest in the context of the development of potential anticancer therapeutics with a new mode of action. They are composed of planar guanine tetrads, allowing a high-affinity targeting by using molecules with a large π surface. However, the extreme topological versatility of guanine quadruplexes impedes a straightforward targeting of particular preselected guanine-rich sequences. We report here a systematic study of a family of luminescent platinum(II) complexes devised to overcome this challenge. By attaching a pendant adenine or thymine nucleobase as a substituent to one of the ligands at the platinum center, an additional recognition site is introduced with the aim of modulating the affinity of the metal complex to different DNA sequences. By comparing different attached nucleobases and a series of linker moieties, first conclusions are drawn with respect to the scope of this approach.

In vivo and in vitro reconstitution of unique key steps in cystobactamid antibiotic biosynthesis

Cystobactamids are myxobacteria-derived topoisomerase inhibitors with potent anti-Gram-negative activity. They are formed by a non-ribosomal peptide synthetase (NRPS) and consist of tailored para-aminobenzoic acids, connected by a unique α-methoxy-l-isoasparagine or a β-methoxy-l-asparagine linker moiety. We describe the heterologous expression of the cystobactamid biosynthetic gene cluster (BGC) in Myxococcus xanthus. Targeted gene deletions produce several unnatural cystobactamids. Using in vitro experiments, we reconstitute the key biosynthetic steps of linker formation and shuttling via CysB to the NRPS. The biosynthetic logic involves a previously uncharacterized bifunctional domain found in the stand-alone NRPS module CysH, albicidin biosynthesis and numerous BGCs of unknown natural products. This domain performs either an aminomutase (AM) or an amide dehydratase (DH) type of reaction, depending on the activity of CysJ which hydroxylates CysH-bound l-asparagine. Furthermore, CysQ O-methylates hydroxyl-l-(iso)asparagine only in the presence of the AMDH domain. Taken together, these findings provide direct evidence for unique steps in cystobactamid biosynthesis.

Lipophilicity Determines Routes of Uptake and Clearance, and Toxicity of an Alpha-Particle-Emitting Peptide Receptor Radiotherapy.

Lipophilicity is explored in the biodistribution (BD), pharmacokinetics (PK), radiation dosimetry (RD), and toxicity of an internally administered targeted alpha-particle therapy (TAT) under development for the treatment of metastatic melanoma. The TAT conjugate is comprised of the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), conjugated to melanocortin receptor 1 specific peptidic ligand (MC1RL) using a linker moiety and chelation of the 225Ac radiometal. A set of conjugates were prepared with a range of lipophilicities (log D 7.4 values) by varying the chemical properties of the linker. Reported are the observations that higher log D 7.4 values are associated with decreased kidney uptake, decreased absorbed radiation dose, and decreased kidney toxicity of the TAT, and the inverse is observed for lower log D 7.4 values. Animals administered TATs with lower lipophilicities exhibited acute nephropathy and death, whereas animals administered the highest activity TATs with higher lipophilicities lived for the duration of the 7 month study and exhibited chronic progressive nephropathy. Changes in TAT lipophilicity were not associated with changes in liver uptake, dose, or toxicity. Significant observations include that lipophilicity correlates with kidney BD, the kidney-to-liver BD ratio, and weight loss and that blood urea nitrogen (BUN) levels correlated with kidney uptake. Furthermore, BUN was identified as having higher sensitivity and specificity of detection of kidney pathology, and the liver enzyme alkaline phosphatase (ALKP) had high sensitivity and specificity for detection of liver damage associated with the TAT. These findings suggest that tuning radiopharmaceutical lipophilicity can effectively modulate the level of kidney uptake to reduce morbidity and improve both safety and efficacy.

Clinical Development of New Antibody-Drug Conjugates in Breast Cancer: To Infinity and Beyond.

Metastatic breast cancer remains an incurable disease, and new therapies are needed. One major limitation of chemotherapy is the toxicity associated with higher dose exposure. Antibody–drug conjugates (ADCs) are a complex and evolving class of agents specifically designed with the objective of delivering antineoplastic medicines in the most precise and selectively targeted way. ADCs are composed of four key components: (1) the target antigen, (2) an antibody construct, (3) a payload (most commonly a cytotoxic agent), and (4) a linker moiety that couples the payload and the antibody. In this review, we discuss the clinical development of ADCs for the treatment of breast cancer, focusing on two recently FDA-approved agents, trastuzumab deruxtecan and sacituzumab govitecan, and discuss the ongoing efforts exploring new agents. Finally, we summarize the current portfolio of clinical trials that could change the algorithm of treatment for early and advanced breast cancer.

Tumor-Penetrating Peptide-Functionalized Ferritin Enhances Antitumor Activity of Paclitaxel.

We describe the development of a neuropilin-1 binding peptide (RGERPPR)-ferritin nanocage that specifically targets tumor cells. Herein, the tumor-penetrating peptide RGERPPR motif was modified at the C-terminal of human H chain ferritin (HFtn) using flexible linker moieties. Since the C-terminal of HFtn is positioned toward the inner cavity, relatively long linkers (GGGGS)4 were used, in which the MMP-2 cleavage site was inserted in the linker. The RGERPPR motif was proved to be exposed outside the protein shell by the effective cleavage at the linker region by MMP-2. The loading of paclitaxel (PTX) and HFtn-mMMP2-RGE was prepared by using the low concentration of urea. In vitro studies demonstrated that HFtn-mMMP2-RGE-PTX nanoparticles exhibited better cytotoxicity and could specifically bind to and be taken up by human lung cancer cells A549 that highly express NRP-1 receptor. Better penetrability and growth inhibitory effect were also verified by the 3D tumor spheroid experiment. The results confirmed that the tumor-targeting and penetration peptide RGERPPR-modified ferritin had great potential in enhancing tumor therapy and could be a promising therapeutic agent.

Fine regulation of linker and donor moieties to construct benzimidazole-based blue emitters for high-efficient organic light-emitting diodes

The investigation and development of novel blue emitters are still necessary for the fabrication of high-efficient organic light-emitting diodes (OLEDs). Benzimidazole and its derivatives have been attracting extensive attention due to the special characterizations to achieve high device efficiency. However, the systematic elucidation of the relationship between structure and properties is rarely reported. In this paper, four benzimidazole derivatives with virus linker and donor units were designed and synthesized, named PI-AN-3-Cz, PI-NP-3-Cz, PI-AN-TPA, and PI-NP-TPA. Their absorption, photoluminescence, electrochemistry, and thermology were systematically studied, and the results were found to be potential candidates for emitters of OLEDs. Interestingly, the fabricated OLEDs with PI-AN-3-Cz as emitter showed the best performance with the efficiencies of 13.75 cd/A, 5.87 lm/W, and 8.55%. Furthermore, it can be observed that these linkers/donors are changed from anthracene to naphthalene/carbazole to triphenylamine, the corresponding emission moved from sky to violet blue with commission international De L’ Eclairage (CIE) of (0.151, 0.055). The findings give a guidance for the preparation of adjustable emission and high-efficient benzimidazole derivatives.

Dibenzodiazepinone-type muscarinic receptor antagonists conjugated to basic peptides: Impact of the linker moiety and unnatural amino acids on M2R selectivity.

The family of human muscarinic acetylcholine receptors (MRs) is characterized by a high sequence homology among the five subtypes (M1R-M5R), being the reason for a lack of subtype selective MR ligands. In continuation of our work on dualsteric dibenzodiazepinone-type M2R antagonists, a series of M2R ligands containing a dibenzodiazepinone pharmacophore linked to small basic peptides was synthesized (64 compounds). The linker moiety was varied with respect to length, number of basic nitrogens (0-2) and flexibility. Besides proteinogenic basic amino acids (Lys, Arg), shorter homologues of Lys and Arg, containing three and two methylene groups, respectively, as well as D-configured amino acids were incorporated. The type of linker had a marked impact on M2R affinity and also effected M2R selectivity. In contrast, the structure of the basic peptide rather determined M2R selectivity than M2R affinity. For example, the most M2R selective compound (UR-CG188, 89) with picomolar M2R affinity (pKi 9.60), exhibited a higher M2R selectivity (ratio of Ki M1R/M2R/M3R/M4R/M5R: 110:1:5200:55:2300) compared to the vast majority of reported M2R preferring MR ligands. For selected ligands, M2R antagonism was confirmed in a M2R miniG protein recruitment assay.

Fragment-Based Drug Design of Selective HDAC6 Inhibitors.

Medicinal chemistry society has enough arguments to justify the usage of fragment-based drug design (FBDD) methodologies for the identification of lead compounds. Since the FDA approval of three kinase inhibitors-vemurafenib, venetoclax, and erdafitinib,FBDD has become a challenging alternative to high-throughput screening methods in drug discovery. The following protocol presents in silico drug design of selective histone deacetylase 6 (HDAC6) inhibitors through a fragment-based approach. To date, structural motifs that are important for HDAC inhibitory activity and selectivity are described as: surface recognition group (CAP group), aliphatic or aromatic linker, and zinc-binding group (ZBG). The main idea of this FBDD method is to identify novel and target-selective CAP groups by virtual scanning of publicly available fragment databases. Template structure used to search for novel heterocyclic and carbocyclic fragments is 1,8-naphthalimide (CAP group of scriptaid, a potent HDAC inhibitor). Herein, the design of HDAC6 inhibitors is based on linking the identified fragments with the aliphatic or aromatic linker and hydroxamic acid (ZBG) moiety. Final selection of potential selective HDAC6 inhibitors is based on combined structure-based (molecular docking) and ligand-based (three-dimensional quantitative structure-activity relationships, 3D-QSAR) techniques. Designed compounds are docked in the active site pockets of human HDAC1 and HDAC6 isoforms, and their docking conformations used to predict their HDAC inhibitory and selectivity profiles through two developed 3D-QSAR models (describing HDAC1 and HDAC6 inhibitory activities).

Design, synthesis, antibacterial activity and toxicity of novel quaternary ammonium compounds based on pyridoxine and fatty acids.

A diverse series of 43 novel "soft antimicrobials" based on quaternary ammonium pyridoxine derivatives which include six-membered acetals and ketals of pyridoxine bound via cleavable linker moieties (amide, ester) with a fragment of fatty carboxylic acid was designed. Nine compounds exhibited invitro promising antibacterial activity against Gram-positive and Gram-negative bacterial strains with MIC values comparable with reference antiseptics miramistin, benzalkonium chloride and chlorohexidine. On various clinical isolates, the lead compounds 6i and 12a exhibited antibacterial activity comparable with that of benzalkonium chloride while higher than that of miramistin. Moreover, 6i and 12a were able to kill bacteria embedded into the matrix of mono- and dual species biofilms. The treatment of bacterial cells by either 6i and 12a lead to fast depolarization of the membrane suggesting that the membrane is an apparent molecular target of compounds. 6i and 12a were non mutagenic neither in SOS-chromotest nor in Ames test and non-toxic invivo at acute oral (LD50>2000mg/kg) and cutaneous administration (LD50>2500mg/kg) on mice. Taken together, our data allow suggesting described active compounds as promising starting point for the new antibacterial agents development.

The discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine cannabinoid type 2 receptor agonist.

The development of selective CB2 receptor agonists is a promising therapeutic approach for the treatment of inflammatory diseases, without CB1 receptor mediated psychoactive side effects. Preliminary structure-activity relationship studies on pyrazoylidene benzamide agonists revealed the -ylidene benzamide moiety was crucial for functional activity at the CB2 receptor. A small library of compounds with varying linkage moieties between the pyrazole and substituted phenyl group has culminated in the discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine agonist 19 (CB2R EC50=19nM, CB1R EC50>10μM). Docking studies have revealed key structural features of the linkage group that are important for potent functional activity.

Discovery of tetrahydroquinolines and benzomorpholines as novel potent RORγt agonists.

The retinoic acid receptor-related orphan receptor γt (RORγt) is an important nuclear receptor that regulates the differentiation of Th17cells and production of interleukin 17(IL-17). RORγt agonists increase basal activity of RORγt and could provide a potential approach to cancer immunotherapy. Herein, hit compound 1 was identified as a weak RORγt agonist during in-house library screening. Changes in LHS core of 1 led to the identification of tetrahydroquinoline compound 6 as a partial RORγt agonist (max. act.=39.3%). Detailed structure-activity relationship on substituent of the LHS core, amide linker and RHS arylsulfonyl moiety was explored and a novel series of tetrahydroquinolines and benzomorpholines was discovered as potent RORγt agonists. Tetrahydroquinoline compound 8g (EC50=8.9±0.4nM, max. act.=104.5%) and benzomorpholine compound 9g (EC50=7.5±0.6nM, max. act.=105.8%) were representative compounds with high RORγt agonistic activity in dual FRET assay, and they showed good activity in cell-based Gal4 reporter gene assay and Th17cell differentiation assay (104.5% activation at 300nM of 8g; 59.4% activation at 300nM of 9g). The binding modes of 8g and 9g as well as the two RORγt inverse agonists accidentally discovered were also discussed.

Discovery of a potent dual inhibitor of wild-type and mutant respiratory syncytial virus fusion proteins through the modulation of atropisomer interconversion properties

The development of effective respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors against both wild-type and the D486N-mutant F protein is urgently required. We recently reported a 15-membered macrocyclic pyrazolo[1,5-a]pyrimidine derivative 4 that exhibited potent anti-RSV activities against not only wild-type, but also D486N-mutant F protein. However, NMR studies revealed that the 15-membered derivative 4 existed as a mixture of atropisomers. An optimization study of the linker moiety between the 2-position of the benzoyl moiety and the 7-position of the pyrazolo[1,5-a]pyrimidine scaffold identified a 16-membered derivative 42c with an amide linker that showed a rapid interconversion of atropisomers. Subsequent optimization of the 5-position of the pyrazolo[1,5-a]pyrimidine scaffold and the 5-position of the benzoyl moiety resulted in the discovery of a potent clinical candidate 60b for the treatment of RSV infections.

Cobamide remodeling in the freshwater microalga Chlamydomonas reinhardtii.

Microalgae are not able to produce cobamides (Cbas, B12 vitamers) de novo. Hence, the production of catalytically active Cba-containing methionine synthase (MetH), which is present in selected representatives, is dependent on the availability of exogenous B12 vitamers. Preferences in the utilization of exogenous Cbas equipped with either adenine or 5,6-dimethylbenzimidazole as lower base have been reported for some microalgae. Here, we investigated the utilization of norcobamides (NorCbas) for growth by the Cba-dependent Chlamydomonas reinhardtii mutant strain (ΔmetE). The growth yields in the presence of NorCbas were lower in comparison to those achieved with Cbas. NorCbas lack a methyl group in the linker moiety of the nucleotide loop. C. reinhardtii was also tested for the remodeling of NorCbas (e.g. adeninyl-norcobamide) in the presence of different benzimidazoles. Extraction of the NorCbas from C. reinhardtii, their purification, and identification confirmed the exchange of the lower base of the vitamers. However, the linker moiety of the NorCbas nucleotide loop was not exchanged. This observation strongly indicates the presence of an alternative mode of Cba deconstruction in C. reinhardtii that differs from the amidohydrolase (CbiZ)-dependent pathway described in Cba-remodeling bacteria and archaea.

Copper‐Catalyzed Modular Access to N‐Fused Polycyclic Indoles and 5‐Aroyl‐pyrrol‐2‐ones via Intramolecular N—H/C—H Annulation with Alkynes: Scope and Mechanism Probes

Summary of main observation and conclusionCopper‐catalyzed intramolecular N—H/C—H annulation with alkynes has been developed. A variety of densely functionalized heterocycles, such as pyrrolo[1,2‐a]indoles, indolo[1,2‐c]quinazolin‐2‐ones, oxazolo[3,4‐a]indoles, and imidazo[1,5‐a]indoles, were synthesized in an atom‐ and step‐economical manner, owing to the high modularized feature of aniline moiety, the linker moiety, as well as the alkyne moiety. By simply changing the oxidant from di‐tert‐butyl peroxide (DTBP) to 2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPO), the reaction could readily be transformed to the aminooxygenation pathway, which grabs one oxygen atom from the TEMPO to generate 5‐aroyl‐pyrrol‐2‐ones. Mechanistic experiments indicate that vinyl radical is involved in this reaction and an amidyl‐radical‐initiated radical cascade might be responsible for this transformation.

Water-soluble galactosamine derivative of β-cyclodextrin as protective ligand and targeted carrier for delivery of toxic anthracycline drug

β-cyclodextrin modified with an electron-rich aromatic triazole linker and targeting moiety (galactosamine) was synthesized and studied as a carrier for the anticancer drug, doxorubicin (DOX), with the aim of targeting the pathological cells, reducing the cardiotoxic side effects and increasing the binding of the drug to DNA. The β-cyclodextrins modified with galactosamine (βCDGAL) are non-toxic and highly soluble in aqueous medium compared to the native βCD and βCD modified only with aromatic moiety, such as triazole linker. Molecular modelling and NMR study gave a deeper insight into the ligand structure, providing an explanation for its increased solubility, and the drug-ligand interactions. The triazole linker strengthened the drug binding and introduced pH dependence of the complex stability constants for βCDGAL derivative, as confirmed by the voltammetry measurements. Spectroscopic studies have shown that entrapment of the DOX in βCDGAL cavity reduces the stability constant of the DOX:Fe(III) complex responsible for the production of cardiotoxic reactive oxygen species and additionally supports the binding of the drug to the double strand DNA. The MTT assay and confocal microscopy results showed that despite encapsulation of the drug in the cyclodextrin molecule, its cytotoxic effect on the liver cancer cell line (HepG2) is comparable to that of the free, non-protected drug.

Discovery of carboxyl-containing biaryl ureas as potent RORγt inverse agonists

GSK805 (1) is a potent RORγt inverse agonist, but a drawback of 1 is its low solubility, leading to a limited absorption in high doses. We have explored detailed structure-activity relationship on the amide linker, biaryl and arylsulfonyl moieties of 1 trying to improve solubility while maintaining RORγt activity. As a result, a novel series of carboxyl-containing biaryl urea derivatives was discovered as potent RORγt inverse agonists with improved drug-like properties. Compound 3i showed potent RORγt inhibitory activity and subtype selectivity with an IC50 of 63.8 nM in RORγ FRET assay and 85 nM in cell-based RORγ-GAL4 promotor reporter assay. Reasonable inhibitory activity of 3i was also achieved in mouse Th17 cell differentiation assay (76% inhibition at 0.3 μM). Moreover, 3i had greatly improved aqueous solubility at pH 7.4 compared to 1, exhibited decent mouse PK profile and demonstrated some in vivo efficacy in an imiquimod-induced psoriasis mice model.