Improved Water Solubility Research Articles

N,N-Disubstituted 4-Sulfamoylbenzoic Acid Derivatives as Inhibitors of Cytosolic Phospholipase A2α: Synthesis, Aqueous Solubility, and Activity in a Vesicle and a Whole Blood Assay.

Cytosolic phospholipase A2α (cPLA2α) is the key enzyme that initiates the arachidonic acid cascade through which pro-inflammatory lipid mediators can be formed. Therefore, cPLA2α is considered an interesting target for the development of anti-inflammatory drugs. Although several effective inhibitors of the enzyme have been developed, none of them has yet reached clinical application. Recently, we have prepared new 4-sulfamoylbenzoic acid derivatives based on a cPLA2α inhibitor found in a ligand-based virtual screening. The most effective of these compounds were now subjected to further variations in which the substitution pattern on the sulfamoyl nitrogen atom was changed.. The new compounds were tested in vitro in a vesicle assay for cPLA2α inhibition as well as for their water solubility, metabolic stability, and selectivity towards related enzymes. In addition, they were evaluated ex vivo in a whole blood assay in which metabolites of the arachidonic acid cascade formed after activation of cPLA2α were quantified using a combined online dilution/ online solid phase extraction HPLC-MS method. Inhibitors with submicromolar inhibitory in vitro potency were found with favourable water solubility and selectivity. However, their efficacy did not match that of the highly effective, known, structurally related cPLA2α inhibitor giripladib, which was also tested as a reference. One advantage of some of the new compounds compared to giripladib was their significantly improved water solubility. When analyzing the substances in the ex vivo whole blood assay, it was found that the obtained inhibition data correlated better with the in vivo results when the phorbol ester 12-Otetradecanoylphorbol- 13-acetate was used for activation of the enzyme in the blood cells instead of the calcium ionophore A23187. New compounds with good activity towards cPLA2α and reasonable physicochemical properties were identified. Overall, the results obtained could be helpful in the development of clinically applicable inhibitors of this enzyme.

NIR-II Fluorescence/Photoacoustic Dual Ratiometric Probes with Unique Recognition Site for Quantitatively Visualizing H2S2 in Vivo.

Hydrogen persulfide (H2S2) plays a significant role in redox biology and signal transduction; therefore, quantitative visualization of H2S2 in the deep tissue of living organisms is essential for obtaining reliable information about relevant pathophysiological processes directly. However, currently reported H2S2 probes are unsuitable for this purpose because of their poor selectivity for many polysulfide species or their short wavelength, which hinders precise imaging in deep tissues. Herein, for the first time, we report a unique H2S2-mediated dithiole formation reaction. Based on this reaction, we construct the first NIR-II fluorescence (FL) and photoacoustic (PA) dual-ratiometric probe (NIR-II-H2S2) for quantitatively visualizing H2S2 in vivo. This probe shows dual-ratiometric NIR-II fluorescence (I840/I1000, 107-fold) and photoacoustic (PA800/PA900, 6.5-fold) responses towards Na2S2 species with high specificity, excellent sensitivity (1.8nM), improved water solubility, and deep-tissue penetration. More importantly, using NIR-II dual-ratiometric FL/PA imaging, we successfully demonstrated that the probe could be used to accurately quantify the fluctuating H2S2 levels in the liver-injury mouse models induced by lipopolysaccharides or metformin drugs. Overall, this study not only presents a promising tool for H2S2-related pathological research, but also provides a unique recognition site that may be generalized for designing more useful H2S2 imaging agents in the future.

NIR‐II Fluorescence/Photoacoustic Dual Ratiometric Probes with Unique Recognition Site for Quantitatively Visualizing H2S2 in Vivo

Hydrogen persulfide (H2S2) plays a significant role in redox biology and signal transduction; therefore, quantitative visualization of H2S2 in the deep tissue of living organisms is essential for obtaining reliable information about relevant pathophysiological processes directly. However, currently reported H2S2 probes are unsuitable for this purpose because of their poor selectivity for many polysulfide species or their short wavelength, which hinders precise imaging in deep tissues. Herein, for the first time, we report a unique H2S2‐mediated dithiole formation reaction. Based on this reaction, we construct the first NIR‐II fluorescence (FL) and photoacoustic (PA) dual‐ratiometric probe (NIR‐II‐H2S2) for quantitatively visualizing H2S2 in vivo. This probe shows dual‐ratiometric NIR‐II fluorescence (I840/I1000, 107‐fold) and photoacoustic (PA800/PA900, 6.5‐fold) responses towards Na2S2 species with high specificity, excellent sensitivity (1.8 nM), improved water solubility, and deep‐tissue penetration. More importantly, using NIR‐II dual‐ratiometric FL/PA imaging, we successfully demonstrated that the probe could be used to accurately quantify the fluctuating H2S2 levels in the liver‐injury mouse models induced by lipopolysaccharides or metformin drugs. Overall, this study not only presents a promising tool for H2S2‐related pathological research, but also provides a unique recognition site that may be generalized for designing more useful H2S2 imaging agents in the future.

Liquid crystal and emulsifying properties of carboxymethyl glucoside as water-soluble surfactant

ABSTRACT Three derivatives of glucosides derived from n-dodecyl alcohol in a highly pure β-anomer were synthesised with the aim to yield the liquid crystalline phase at ambient temperature with improved water solubility. Effect of variation in headgroup polarity on thermal properties, liquid crystalline phases, and structures of these derivatives of n-dodecyl β-D-glucoside (β-GlcC12) has been examined through differential scanning calorimetry, optical polarising microscopy, and small- and wide-angle X-ray scattering, respectively. Derivative bearing two carboxymethyl and two hydroxyl groups at the sugar ring i.e. n-dodecyl 2,3-bis-O-[carboxymethyl]-β-D-glucopyranoside (2,3-diCOOH-β-GlcC12) exhibited lamellar phase at the room temperature in anhydrous condition by significantly reduced the melting and clearing temperatures compared to parent compound β-GlcC12. Under excess water condition, 2,3-diCOOH-β-GlcC12 was completely soluble to form a normal micellar solution. We further investigated its foaming performance and emulsifying ability in n-octane, n-dodecane, and n-hexadecane as the oil phase. Both aqueous solution of 2,3-diCOOH-β-GlcC12 emulsified with n-dodecane and n-hexadecane formed oil-in-water emulsion layer of more than 95% of the total system volume with n-dodecane/water system consistently maintains smaller particle sizes and a narrower polydispersity index. This supports the stronger emulsifying ability and better colloidal stability of the 2,3-diCOOH-β-GlcC12 in the n-dodecane/water system than in the n-hexadecane/water system.

Engineering an oncolytic adenoviral platform for precise delivery of antisense peptide nucleic acid to modulate PD-L1 overexpression in cancer cells

Cancer immunotherapy is focused on stimulating the immune system against cancer cells by exploiting immune checkpoint mechanisms. PD-1/PD-L1 is one of the most known immune checkpoints due to the widespread upregulation of the Programmed Death Ligand 1 (PD-L1) transmembrane protein in cancer tissues. Accordingly, taking advantage of the ability of oncolytic adenoviruses (OAd) to specifically infect and kill tumor cells over healthy ones, here, we developed a targeted delivery platform based on OAd to selectively deliver in cancer cells an antisense peptide nucleic acid (PNA) targeting the PD-L1 mRNA. The antisense PNA was modified with a six-lysine tail to improve water solubility and binding affinity to the polyanionic surface of the OAd carrier. Dynamic light scattering measurements confirmed the effective binding of the PNA cargo to OAd. Flow cytometry analysis evaluated the impact on PD-L1 protein expression in A549 and SK-OV3 cancer cell lines post-incubation with the OAd/PNA system. Statistically significant PD-L1 downregulation was observed in SK-OV3 cells treated with OAd-delivered PNA, surpassing the effect of free PNA. Confocal microscopy showed the cytoplasmic localization of OAd-delivered PNA, supporting the proposed antisense mechanism for PD-L1 downregulation. This targeted delivery system holds potential for enhancing the effectiveness of cancer immunotherapy.

Meta-substituted thienoviologen with enhanced radical stability via π-π interaction modulation for neutral aqueous organic flow batteries

The aqueous organic redox flow batteries (AORFBs) are recognized as the most promising large-scale storage technology for long-duration energy storage (LDES). Although viologen derivatives are widely used as anolyte materials for AORFBs, their practical application is strongly limited by weak conjugation and unstable radicals. Here, we present a novel thienoviologen derivative, [(NPr)2SV]Cl4, achieved utilizing a meta-substitution approach based on the pristine viologen derivatives ( [(NPr)2V]Cl4). Compared to other ortho- and para-substitution methods, this strategy features a locked plane configuration (0.14°), effectively regulating π-π interactions and suppressing reactivity between radical and oxygen, which is confirmed via X-ray single-crystal structural analyses, spectroscopy techniques, molecular dynamics simulation accompanied by linear ion trap mass spectrometry experiments. Additionally, the meta-substituted [(NPr)2SV]Cl4 significantly improves water solubility (2.39 M), enhances aromaticity, and extends radical lifetime compared with para-substituted [(NPr)2TV]Cl4. Consequently, the cycling stability of the [(NPr)2SV]Cl4-based AORFB over 2500 cycles is 4.1 times higher than that of [(NPr)2TV]Cl4. Furthermore, the 0.5 M battery delivers an impressive 99.83% capacity retention during 200 cycles and a power density of 147 mW cm-2.

Effect of conformational landscape on the polymorphism and monomorphism of tizanidine cocrystallization outcomes

Molecular conformational diversity plays a crucial role in both polymorphic nucleation and cocrystal formation during the cocrystallization process. However, the relationship between molecular conformation and cocrystallization polymorphism is not well-explored. Herein, the impact of molecular conformational landscapes on cocrystallization outcomes was investigated using tizanidine (TZND) as model compound. Four coformers, namely maleic acid (MA), salicylic acid (SA), p-hydroxybenzoic acid (pHBA), and heptanedioic acid (HDA), were employed and five salt forms were developed for the first time. Compared with TZND, all five salts showed significantly improved water solubility and dissolution rate. The cocrystallization behavior of TZND varied with each coformer: MA exhibited solvent-dependent polymorphism, while SA, pHBA, and HDA showed solvent-independent monomorphism. Crystal structure and conformational analyses revealed the conformational variation of TZND across different cocrystallization outcomes. Molecular dynamics simulations and quantum chemical calculations demonstrated that the interplay between solvent effects and coformer interactions determines the dominant conformations of TZND. The cocrystallization nucleation process was also examined, and the molecular mechanism that explains both polymorphism and monomorphism in the cocrystallization of TZND was proposed.

Recent Advances in the Synthesis and Optical Applications of Acridine-based Hybrid Fluorescent Dyes.

Acridine-based hybrid fluorescent dyes represent a category of dyes that integrate the acridine chromophore with other functional groups or materials to enhance their fluorescence properties. These dyes have garnered substantial attention across various domains, encompassing bioimaging, sensing, and optoelectronics. In recent years, researchers have directed their efforts toward fabricating acridine-based hybrid fluorescent dyes with improved water solubility, biocompatibility, and targeting capabilities. These advancements have facilitated their utilization in biological imaging applications, such as monitoring cellular processes, investigating protein-protein interactions, and detecting specific biomolecules. This review delineates the recent progress in synthesizing acridine-based hybrid fluorescent dyes and their applications in optical properties over the past decade. This review is anticipated to catalyze the development of innovative fluorescent materials featuring heightened properties and functionalities.

Photocleavable Protecting Groups Using a Sulfite Self‐Immolative Linker for High Uncaging Quantum Yield and Aqueous Solubility

AbstractUsing light as an external stimulus to control (bio)chemical processes offers many distinct advantages. Most importantly, it allows for spatiotemporal control simply through operating the light source. Photocleavable protecting groups (PPGs) are a cornerstone class of compounds that are used to achieve photocontrol over (bio)chemical processes. PPGs are able to release a payload of interest upon light irradiation. The successful application of PPGs hinges on their efficiency of payload release, captured in the uncaging Quantum Yield (QY). Heterolytic PPGs efficiently release low pKa payloads, but their efficiency drops significantly for payloads with higher pKa values, such as alcohols. For this reason, alcohols are usually attached to PPGs via a carbonate linker. The self‐immolative nature of the carbonate linker results in concurrent release of CO2 with the alcohol payload upon irradiation. We introduce herein novel PPGs containing sulfites as self‐immolative linkers for photocaged alcohol payloads, for which we discovered that the release of the alcohol proceeds with higher uncaging QY than an identical payload released from a carbonate‐linked PPG. Furthermore, we demonstrate that uncaging of the sulfite‐linked PPGs results in the release of SO2 and show that the sulfite linker improves water solubility as compared to the carbonate‐based systems.

Improving Water Solubility of Docosahexaenoic Acid with Chickpea Protein Isolates Deamidated by Protein-glutaminase

Improving Water Solubility of Docosahexaenoic Acid with Chickpea Protein Isolates Deamidated by Protein-glutaminase

Photocleavable Protecting Groups Using a Sulfite Self-Immolative Linker for High Uncaging Quantum Yield and Aqueous Solubility.

Using light as an external stimulus to control (bio)chemical processes offers many distinct advantages. Most importantly, it allows for spatiotemporal control simply through operating the light source. Photocleavable protecting groups (PPGs) are a cornerstone class of compounds that are used to achieve photocontrol over (bio)chemical processes. PPGs are able to release a payload of interest upon light irradiation. The successful application of PPGs hinges on their efficiency of payload release, captured in the uncaging Quantum Yield (QY). Heterolytic PPGs efficiently release low pKa payloads, but their efficiency drops significantly for payloads with higher pKa values, such as alcohols. For this reason, alcohols are usually attached to PPGs via a carbonate linker. The self-immolative nature of the carbonate linker results in concurrent release of CO2 with the alcohol payload upon irradiation. We introduce herein novel PPGs containing sulfites as self-immolative linkers for photocaged alcohol payloads, for which we discovered that the release of the alcohol proceeds with higher uncaging QY than an identical payload released from a carbonate-linked PPG. Furthermore, we demonstrate that uncaging of the sulfite-linked PPGs results in the release of SO2 and show that the sulfite linker improves water solubility as compared to the carbonate-based systems.

Camptothecin and its derivatives: Advancements, mechanisms and clinical potential in cancer therapy.

Camptothecin (CPT), an alkaloid isolated from the Camptotheca tree, has demonstrated significant anticancer properties in a range of malignancies. However, its therapeutic efficacy is limited by its hydrophobicity, poor bioavailability, and systemic toxicity. Derivatives, analogues, and nanoformulations of CPT have been synthesized to overcome these limitations. The aim of this review is to comprehensively analyze existing studies to evaluate the therapeutic efficacy, mechanistic aspects, and clinical potential of CPT and its modified forms, including derivatives, analogues, and nanoformulations, in cancer treatment. A comprehensive literature review was performed using PubMed/Medline, Scopus, and Web of Science databases; articles were selected based on specific inclusion criteria, and data were extracted on the pharmacological profile, clinical studies, and therapeutic efficacy of CPT and its different forms. Current evidence suggests that derivatives and analogues of CPT have improved water solubility, bioavailability, and reduced systemic toxicity compared to CPT. Nanoformulations further enhance targeted delivery and reduce off-target effects. Clinical trials indicate promising outcomes with enhanced survival rates and lower side effects. CPT and its modified forms hold significant promise as potent anticancer agents. Ongoing research and clinical trials are essential for establishing their long-term efficacy and safety; the evidence overwhelmingly supports further development and clinical testing of these compounds.

A Review on Recent Trends in Photo-Drug Efficiency of Advanced Biomaterials in Photodynamic Therapy of Cancer.

Photodynamic Therapy (PDT) has emerged as a highly efficient and non-invasive cancer treatment, which is crucial considering the significant global mortality rates associated with cancer. The effectiveness of PDT primarily relies on the quality of the photosensitizers employed. When exposed to appropriate light irradiation, these photosensitizers absorb energy and transition to an excited state, eventually transferring energy to nearby molecules and generating Reactive Oxygen Species (ROS), including singlet oxygen [1O2]. The ability to absorb light in visible and nearinfrared wavelengths makes porphyrins and derivatives useful photosensitizers for PDT. Chemically, Porphyrins, composed of tetra-pyrrole structures connected by four methylene groups, represent the typical photosensitizers. The limited water solubility and bio-stability of porphyrin photosensitizers and their non-specific tumor-targeting properties hinder PDT effectiveness and clinical applications. Therefore, a wide range of modification and functionalization techniques have been used to maximize PDT efficiency and develop multidimensional porphyrin-based functional materials. Recent progress in porphyrin-based functional materials has been investigated in this review paper, focusing on two main aspects including the development of porphyrinic amphiphiles that improve water solubility and biocompatibility, and the design of porphyrin-based polymers, including block copolymers with covalent bonds and supramolecular polymers with noncovalent bonds, which provide versatile platforms for PDT applications. The development of porphyrin-based functional materials will allow researchers to significantly expand PDT applications for cancer therapy by opening up new opportunities. With these innovations, porphyrins will overcome their limitations and push PDT to the forefront of cancer treatment options.

Nanocochleates as novel delivery vehicles for enhancement of water solubility, stability and controlled release of dihydromyricetin in gastrointestinal tract

Dihydromyricetin (DHM) possesses impressive antioxidant and anti-inflammatory properties; however, its effectiveness is limited by poor bioavailability. Liposomes improve the solubility and stability of insoluble bioactives but encounter challenges in gastrointestinal fluids after oral administration. Consequently, DHM-loaded nanocochleates were fabricated to enhance the solubility, stability, and release behavior of DHM. The nanoliposomes exhibited an entrapment efficiency (EE) ranging from 85.64 % to 88.79 %, a particle size between 136.20 and 150.70 nm, a polydispersity index (PDI) of 0.36 to 0.43, and a zeta potential of –6.82 to –11.13 mV. In contrast, the cylindrical-shaped nanocochleates demonstrated an EE ranging from 74.94 % to 84.64 %, a particle size between 239.07 and 571.43 nm, a PDI from 0.16 to 0.61, and a zeta potential ranging from –21.97 to –27.10 mV. The nanocochleates exhibited improved water solubility (64.75 %) and retained antioxidant activity (41.38 %) compared to free DHM. Additionally, they demonstrated enhanced stability of DHM compared to nanoliposomes during 30 days of storage. Fourier transform infrared spectroscopy and differential scanning calorimetry confirmed that DHM was encapsulated within nanocochleate structures via ionic and chemical interactions. X-ray diffraction revealed a distinct organization of the nanocochleates in comparison to the nanoliposomes. The release of DHM from nanocochleates demonstrated a prolonged and controlled release in simulated gastrointestinal medium, unlike the burst release observed with nanoliposomes. This study hightlighted the potential of nanocochleates as novel delivery vehicles for enhancing the stability and bioavailability of DHM. It also offered a unique perspective on developing functional food formulations that utilize nanocochleates as promising nanocarriers for bioactives.

Enhanced Plasma Stability and Potency of Aryl/Acyloxy Prodrugs of a BTN3A1 Ligand.

While ester-based phosphonate prodrugs excel at delivering payloads into cells, their instability in plasma is a hurdle for their advancement. Here, we synthesized new aryl/acyloxy prodrugs of a phosphonate BTN3A1 ligand. We evaluated their phosphoantigen potency by flow cytometry and ELISA and their plasma and cellular metabolism by LC-MS. These compounds displayed low nanomolar to high picomolar potency. Addition of a p-isopropyl group to the phenyl substituent and use of cyclohexyl or p-methoxybenzyl groups as the acyloxy substituent significantly increased human, but not mouse or rat, plasma stability without negatively impacting potency. Combinations of these prodrug moieties further improved stability, with the best combination achieving a half-life of over 12 h in human plasma, a marked improvement on prior compounds. In contrast, oxane analogs improved water solubility and cellular payload delivery but remained unstable in human plasma. The studies suggest that certain ester-based phosphonate prodrugs quickly deliver active payloads inside cells and show substantial stability in human plasma.

In vitro anthelmintic activity of hydroethanolic extract of Artemisia herba aba and Juniperus phoenicea on abomasal Teladorsagia circumcincta of sheep.

The present study aimed to evaluate the in vitro anthelmintic activity of Juniperus phoenicea and Artemisia herba-alba against abomasal nematodes collected from naturally infected sheep. The anthelmintic activities of the extracts were assessed using egg hatch inhibition (EHIA) and adult motility assays (AMA) against Teladorsagia circumcincta. The parasites were stored in phosphate-buffered saline (PBS) until the in vitro assessment began. The leaf powders of J. phoenicea and A. herba-alba were extracted using the maceration procedure. Briefly, the leaf powders were mixed with a sufficient quantity of 99% ethanol and distilled water (80%/20%). The extracts were dissolved in a 3% dimethyl sulfoxide (DMSO) solution to improve water solubility. The hydroethanolic extracts were tested at concentrations of 1.562, 3.125, 6.25, 12.5, and 25 mg/ml. Adult motile worms were individually subjected to each treatment at laboratory temperature. The PBS and albendazole (25 mg/ml) were prepared and used as negative and positive controls, respectively. The test was repeated five times for each concentration. The results showed that both plant extracts exhibited anthelmintic effects. A. herba-alba extract at 25 mg/ml inhibited the motility of all T. circumcincta adult worms within 1 hour of administration, while J. phoenicea extract caused 100% mortality of adult worms after 4 hours at the same concentration. Neither of the extracts, at 1.562 mg/ml, had any inhibitory effect on motility. At 25 mg/ml, the A. herba-alba (98.67%) and J. phoenicea (96.24%) showed high activity with an inhibitory effect on hatchability compared to the other tested concentrations. The findings of the present study showed that hydroethanolic extracts of A. herba-alba and J. phoenicea leaves had in vitro anthelmintic activity on eggs and adult T. circumcincta of sheep.

Characterization of naproxen salts with amino acid esters and their application in topical skin preparations

In the study, the modification of naproxen (NAP) with esters of four amino acids (AAs): glycine (GlyOiPr), L-proline (ProOiPr), L-leucine (LeuOiPr), and L-serine (SerOiPr) isopropyl ester was performed to improve water solubility and enhance the permeation of the drug through the skin in comparison to the parent NAP. The NAP derivatives were prepared using the equimolar ratio of the components. In-depth NMR and FTIR analysis revealed that the salts formed with the proton transfer from the carboxylic group of NAP to the amine group of the appropriate AA ester. The NAP salts exhibited improved solubility in water and PBS solution (pH 7.4) when compared to parent NAP. The values of the partition coefficient (log PO/W) for prepared salts were lower than for NAP, however, the salts maintained hydrophobic character determined by the positive values of log P. The In vitro permeation through the pig skin performed in Franz diffusion cells showed that all NAP salts exhibited a higher cumulative mass of permeated NAP (Q24h) than the parent acid. The highest permeation value was noted for [ProOiPr][NAP], with a pseudo-steady state flux (Jss) 32.5 µg NAP cm−2h−1, and Q24h = 246.4 µg NAP cm−2, it was 2.5 % of the applied dose. Moreover, topical preparations with [ProOiPr][NAP] and NAP were prepared based on two vehicles − Celugel® and Pentravan®- approved in pharmacy recipes. The permeation experiments through the Strat-M® showed, that both the Jss and Q24h of permeated drug from preparations containing [ProOiPr][NAP], were statistically several times greater than from the respective preparations with the unmodified acid. Additionally, preparations with [ProOiPr][NAP] provided significantly improved permeation of NAP than two commercial preparations, one of which contained naproxen as the acid and the other – as the sodium salt.

Randomly methylated β-cyclodextrin improves water – solubility, cellular protection and mucosa permeability of idebenone

Neurodegenerative diseases such as Alzheimer’s are very common today. Idebenone (IDE) is a potent antioxidant with good potential for restoring cerebral efficiency in cases of these and other medical conditions, but a serious drawback for the clinical use of IDE in neurological disorders lies in its scarce water solubility, which greatly inhibits its bioavailability. In this work, we prepared the inclusion complex of IDE with randomly methylated β-cyclodextrin (RAMEB), resulting in improved water solubility of the included drug; then its in vitro biological activity and ex vivo permeability was evalutated. The solid complex was characterized through FT-IR spectroscopy, Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC). A 78-fold improvement of the solubility of IDE in water resulted, together with a strong 1:1 host–guest interaction (association constant of 12630 M−1), and dissolution of the complex within 15 min, all evidenced during the in-solution studies. Biological in vitro studies were then performed on differentiated human neuroblastoma cells (SH-SY5Y) subjected to oxidative stress. Pretreatment with IDE/RAMEB positively affected cell viability, promoted the nuclear translocation of Nrf2, and increased the levels of GSH as well as those of the endogenous antioxidant enzymes Mn-SOD and HO-1. Lastly, the complexation significantly improved the permeation of IDE through isolated rat nasal mucosa.

Design, synthesis and antimycobacterial activity of novel benzothiazinones with improved water solubility

Nitrobenzothiazinones (BTZs) represent a novel type of antitubercular agents targeting DprE1. Two clinical candidates BTZ043 and PBTZ169, as well as many other BTZs showed potent anti-TB activity, but they are all highly lipophilic and their poor aqueous solubility is still a serious issue need to be addressed. Here, we designed and synthesized a series of new BTZ derivatives, wherein a hydrophilic COOH or NH2 group is directly attached to the oxime moiety of TZY-5-84 discovered in our lab, through various linkers. Two compounds 1a and 3 were first reported to possess excellent activity against MTB H37Rv and MDR-MTB strains (MIC: <0.029–0.095 μM), low toxicity and acceptable oral PK profiles, as well as significantly improved water solubility (1200 and > 2000 μg/mL, respectively), suggesting they may serve as promising hydrophilic BTZs for further antitubercular drug discovery.

Solubility, the Main Concern for Poorly Water-soluble Drugs: Techniques and Alternatives

: The most important variable that affects a drug's bioavailability is its aqueous solubility. One of the biggest issues facing the pharmaceutical business is improving water solubility, which is the key to improving therapeutic efficacy. During the first screening procedure, over 50% of recently created medications are discovered to be insoluble or weakly soluble. The solubility of the medicine can be increased using a variety of techniques. The method entails both chemical and physical drug modifications. Any medicine that is absorbed must be present at the absorption site in the form of a solution. Poorly soluble medications can be made more soluble using a variety of approaches, like physical and chemical alterations to the drug and other strategies. Using a surfactant, complexation, and so on are examples of solid dispersion. The choice of a solubility-improving technology is influenced by pharmacological properties, absorption sites, and the requirements for the dosage form. In order to serve as a quick reference, this study attempted to gather information on various solubility improvement methods and organize it systematically.