Thiacalixarene Carboxylic Acid Derivatives as Inhibitors of Lysozyme Fibrillation.

Amyloid fibroproliferation leads to organ damage and is associated with a number of neurodegenerative diseases affecting populations worldwide. There are several ways to protect against fibril formation, including inhibition. A variety of organic compounds based on molecular recognition of amino acids within the protein have been proposed for the design of such inhibitors. However, the role of macrocyclic compounds, i.e., thiacalix[4]arenes, in inhibiting fibrillation is still almost unknown. In the present work, the use of water-soluble thiacalix[4]arene derivatives for the inhibition of hen egg-white lysozyme (HEWL) amyloid fibrillation is proposed for the first time. The binding of HEWL by the synthesized thiacalix[4]arenes (logKa = 5.05-5.13, 1:1 stoichiometry) leads to the formation of stable supramolecular systems capable of stabilizing the protein structure and protecting against fibrillation by 29-45%. The macrocycle conformation has little effect on protein binding strength, and the native HEWL secondary structure does not change via interaction. The synthesized compounds are non-toxic to the A549 cell line in the range of 0.5-250 µg/mL. The results obtained may be useful for further investigation of the anti-amyloidogenic role of thiacalix[4]arenes, and also open up future prospects for the creation of new ways to prevent neurodegenerative diseases.

A prospective study on the early evaluation of response to androgen receptor-targeted agents with 11C-Choline, 68Ga-PSMA, and 18F-FACBC PET in metastatic castration-resistant prostate cancer: a single-center experience.

BACKGROUND: The early identification of responsive and resistant patients to androgen receptor-targeting agents (ARTA) in metastatic castration-resistant prostate cancer (mCRPC) is not completely possible with prostate-specific antigen (PSA) assessment and conventional imaging. Considering its ability to determine metabolic activity of lesions, positron emission tomography (PET) assessment might be a promising tool. PATIENTS AND METHODS: We carried out a monocentric prospective study in patients with mCRPC treated with ARTA to evaluate the role of different PET radiotracers: 49 patients were randomized to receive 11C-Choline, Fluorine 18 fluciclovine (anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid - FACBC) (18F-FACBC), or Gallium-68-prostate-specific-membrane-antigen (68Ga-PSMA) PET, one scan before therapy and one 2 months later. The primary aim was to investigate the performance of three novel PET radiotracers for the early evaluation of response to ARTA in metastatic CRPC patients; the outcome evaluated was biochemical response (PSA reduction ≥50%). The secondary aim was to investigate the prognostic role of several semiquantitative PET parameters and their variations with the different radiotracers in terms of biochemical progression-free survival (bPFS) and overall survival (OS). The study was promoted by the Italian Department of Health (code RF-2016-02364809). RESULTS: Regarding the primary endpoint, at log-rank test a statistically significant correlation was found between metabolic tumor volume (MTV) (P = 0.018) and total lesion activity (TLA) (P = 0.025) percentage variation among the two scans with 68Ga-PSMA PET and biochemical response. As for the secondary endpoints, significant correlations with bPFS were found for 68Ga-PSMA total MTV and TLA at the first scan (P = 0.001 and P = 0.025, respectively), and MTV percentage variation (P = 0.031). For OS, statistically significant correlations were found for different 68Ga-PSMA and 18F-FACBC parameters and for major maximum standardized uptake value at the first 11C-Choline PET scan. CONCLUSIONS: Our study highlighted that 11C-Choline, 68Ga-PSMA, and 18F-FACBC semiquantitative PET parameters and their variations present a prognostic value in terms of OS and bPFS, and MTV and TLA variations with 68Ga-PSMA PET a correlation with biochemical response, which could help to assess the response to ARTA.

Coordinative Compounds Based on Unsaturated Carboxylate with Versatile Biological Applications.

This review presents an overview of the biological applications of coordinative compounds based on unsaturated carboxylates accompanied by other ligands, usually N-based heterocyclic species. The interest in these compounds arises from the valuable antimicrobial and antitumor activities evidenced by some species, as well as from their ability to generate metal-containing polymers suitable for various medical purposes. Therefore, we describe the recently discovered aspects related to the synthesis, structure, and biological activity of a wide range of unsaturated carboxylate-containing species and metal ions, originating mostly from 3d series. The unsaturated carboxylates encountered in coordinative compounds are acrylate, methacrylate, fumarate, maleate, cinnamate, ferulate, coumarate, and itaconate. Regarding the properties of the investigated compounds, it is worth mentioning the good ability of some to inhibit the development of resistant strains or microbial biofilms on inert surfaces or, even more, exert antitumor activity against resistant cells. The ability of some species to intercalate into DNA strands as well as to scavenge ROS species is also addressed.

Design, synthesis, and biological evaluation of 5-(1H-indol-5-yl)isoxazole-3-carboxylic acids as novel xanthine oxidase inhibitors.

Xanthine oxidase (XO) is a key enzyme for the production of uric acid in the human body. XO inhibitors (XOIs) are clinically used for the treatment of hyperuricemia and gout, as they can effectively inhibit the production of uric acid. Previous studies indicated that both indole and isoxazole derivatives have good inhibitory effects against XO. Here, we designed and synthesized a novel series of N-5-(1H-indol-5-yl)isoxazole-3-carboxylic acids according to bioisosteric replacement and hybridization strategies. Among the obtained target compounds, compound 6c showed the best inhibitory activity against XO with an IC50 value of 0.13 µM, which was 22-fold higher than that of the classical antigout drug allopurinol (IC50 = 2.93 µM). Structure-activity relationship analysis indicated that the hydrophobic group on the nitrogen atom of the indole ring is essential for the inhibitory potencies of target compounds against XO. Enzyme kinetic studies proved that compound 6c acted as a mixed-type XOI. Molecular docking studies showed that the target compound 6c could not only retain the key interactions similar to febuxostat at the XO binding site but also generate some new interactions, such as two hydrogen bonds between the oxygen atom of the isoxazole ring and the amino acid residues Ser876 and Thr1010. These results indicated that 5-(1H-indol-5-yl)isoxazole-3-carboxylic acid might be an efficacious scaffold for designing novel XOIs and compound 6c has the potential to be used as a lead for further the development of novel anti-gout candidates.

Design, Synthesis, and Mechanistic Studies of (R)-3-Amino-5,5-difluorocyclohex-1-ene-1-carboxylic Acid as an Inactivator of Human Ornithine Aminotransferase.

Human ornithine aminotransferase (hOAT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme, has been shown to play an essential role in the metabolic reprogramming and progression of hepatocellular carcinoma (HCC). HCC accounts for approximately 75% of primary liver cancers and is within the top three causes of cancer death worldwide. As a result of treatment limitations, the overall 5-year survival rate for all patients with HCC is under 20%. The prevalence of HCC necessitates continued development of novel and effective treatment methods. In recent years, the therapeutic potential of selective inactivation of hOAT has been demonstrated for the treatment of HCC. Inspired by previous increased selectivity for hOAT by the expansion of the cyclopentene ring scaffold to a cyclohexene, we designed, synthesized, and evaluated a series of novel fluorinated cyclohexene analogues and identified (R)-3-amino-5,5-difluorocyclohex-1-ene-1-carboxylic acid as a time-dependent inhibitor of hOAT. Structural and mechanistic studies have elucidated the mechanism of inactivation of hOAT by 5, resulting in a PLP-inactivator adduct tightly bound to the active site of the enzyme. Intact protein mass spectrometry, 19F NMR spectroscopy, transient state kinetic studies, and X-ray crystallography were used to determine the structure of the final adduct and elucidate the mechanisms of inactivation. Interestingly, despite the highly electrophilic intermediate species conferred by fluorine and structural evidence of solvent accessibility in the hOAT active site, Lys292 and water did not participate in nucleophilic addition during the inactivation mechanism of hOAT by 5. Instead, rapid aromatization to yield the final adduct was favored.

Allosteric Activation of α7 Nicotinic Acetylcholine Receptors by Novel 2-Arylamino-thiazole-5-carboxylic Acid Amide Derivatives for the Improvement of Cognitive Deficits in Mice.

Enhancing α7 nAChR function serves as a therapeutic strategy for cognitive disorders. Here, we report the synthesis and evaluation of 2-arylamino-thiazole-5-carboxylic acid amide derivatives 6-9 that as positive allosteric modulators (PAMs) activate human α7 nAChR current expressed in Xenopus ooctyes. Among the 4-amino derivatives, a representative atypical type I PAM 6p exhibits potent activation of α7 current with an EC50 of 1.3 µM and the maximum activation effect on the current over 48-fold in the presence of acetylcholine (100 µM). The structure-activity relationship (SAR) analysis reveals that the 4-amino group is crucial for the allosteric activation of α7 currents by compound 6p as the substitution of 4-methyl group results in its conversion to compound 7b (EC50 = 2.1 µM; max effect: 58-fold) characterized as a typical type I PAM. Furthermore, both 6p and 7b are able to rescue auditory gating deficits in mouse schizophrenia-like model of acoustic startle prepulse inhibition.

Biosynthesis of Chryseno[2,1,c]oxepin-12-Carboxylic Acid from Glycyrrhizic Acid in Aspergillus terreus TMZ05-2, and Analysis of Its Anti-inflammatory Activity.

Glycyrrhizic acid, glycyrrhetinic acid, and their oxo, ester, lactone, and other derivatives, are known for their anti-inflammatory, anti-oxidant, and hypoglycemic pharmacological activities. In this study, chryseno[2,1-c]oxepin-12-carboxylic acid (MG) was first biosynthesized from glycyrrhizic acid through sequential hydrolysis, oxidation, and esterification using Aspergillus terreus TMZ05-2, providing a novel in vitro biosynthetic pathway for glycyrrhizic acid derivatives. Assessing the influence of fermentation conditions and variation of strains during culture under stress-induction strategies enhanced the final molar yield to 88.3% (5 g/L glycyrrhizic acid). CCK8 assays showed no cytotoxicity and good cell proliferation, and anti-inflammatory experiments demonstrated strong inhibition of NO release (36.3%, low-dose MG vs. model), transcriptional downregulation of classical effective cellular factors tumor necrosis factor-α (TNF-α; 72.2%, low-dose MG vs. model), interleukin-6 (IL-6; 58.3%, low-dose MG vs. model) and interleukin-1ß (IL-1ß; 76.4%, low-dose MG vs. model), and decreased abundance of P-IKK-α, P-IKB-α, and P-P65 proteins, thereby alleviating inflammatory responses through the NF-κB pathway in LPS-induced RAW264.7 cells. The findings provide a reference for the biosynthesis of lactone compounds from medicinal plants.

Identification of new 5-(2,6-dichlorophenyl)-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-7-carboxylic acids as p38α MAPK inhibitors: Design, synthesis, antitumor evaluation, molecular docking and in silico studies.

In pursuit of discovering novel scaffolds that demonstrate potential inhibitory activity against p38α MAPK and possess strong antitumor effects, we herein report the design and synthesis of new series of 17 final target 5-(2,6-dichlorophenyl)-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-7-carboxylic acids (4-20). Chemical characterization of the compounds was performed using FT-IR, NMR, elemental analyses and mass spectra of some representative examples. With many compounds showing potential inhibitory activity against p38α MAPK, two derivatives, 8 and 9, demonstrated the highest activity (>70 % inhibition) among the series. Derivative 9 displayed IC50 value nearly 2.5 folds more potent than 8. As anticipated, they both showed explicit interactions inside the kinase active site with the key binding amino acid residues. Screening both compounds for cytotoxic effects, they exhibited strong antitumor activities against lung (A549), breast (MCF-7 and MDA MB-231), colon (HCT-116) and liver (Hep-G2) cancers more potent than reference 5-FU. Their noticeable strong antitumor activity pointed out to the possibility of an augmented DNA binding mechanism of antitumor action besides their kinase inhibition. Both 8 and 9 exhibited strong ctDNA damaging effects in nanomolar range. Further mechanistic antitumor studies revealed ability of compounds 8 and 9 to arrest cell cycle in MCF-7 cells at S phase, while in HCT-116 treated cells at G0-G1 and G2/M phases. They also displayed apoptotic induction effects in both MCF-7 and HCT-116 with total cell deaths more than control untreated cells in reference to 5-FU. Finally, the compounds were tested for their anti-migratory potential utilizing wound healing assay. They induced a significant decrease in wound closure percentage after 24 h treatment in the examined cancer cells when compared to untreated control MCF-7 and HCT-116 cells better than 5-FU. In silico computation of physicochemical parameters revealed the drug-like properties of 8 and 9 with no violation to Lipinski's rule of five as well as their tolerable ADMET parameters, thus suggesting their utilization as potential future drug leads amenable for further optimization and development.

Bacillus sp. G2112 Detoxifies Phenazine-1-carboxylic Acid by N5 Glucosylation.

Microbial symbionts of plants constitute promising sources of biocontrol organisms to fight plant pathogens. Bacillus sp. G2112 and Pseudomonas sp. G124 isolated from cucumber (Cucumis sativus) leaves inhibited the plant pathogens Erwinia and Fusarium. When Bacillus sp. G2112 and Pseudomonas sp. G124 were co-cultivated, a red halo appeared around Bacillus sp. G2112 colonies. Metabolite profiling using liquid chromatography coupled to UV and mass spectrometry revealed that the antibiotic phenazine-1-carboxylic acid (PCA) released by Pseudomonas sp. G124 was transformed by Bacillus sp. G2112 to red pigments. In the presence of PCA (>40 µg/mL), Bacillus sp. G2112 could not grow. However, already-grown Bacillus sp. G2112 (OD600 > 1.0) survived PCA treatment, converting it to red pigments. These pigments were purified by reverse-phase chromatography, and identified by high-resolution mass spectrometry, NMR, and chemical degradation as unprecedented 5N-glucosylated phenazine derivatives: 7-imino-5N-(1'ß-D-glucopyranosyl)-5,7-dihydrophenazine-1-carboxylic acid and 3-imino-5N-(1'ß-D-glucopyranosyl)-3,5-dihydrophenazine-1-carboxylic acid. 3-imino-5N-(1'ß-D-glucopyranosyl)-3,5-dihydrophenazine-1-carboxylic acid did not inhibit Bacillus sp. G2112, proving that the observed modification constitutes a resistance mechanism. The coexistence of microorganisms-especially under natural/field conditions-calls for such adaptations, such as PCA inactivation, but these can weaken the potential of the producing organism against pathogens and should be considered during the development of biocontrol strategies.

On the potential role of naturally occurring carboxylic organic acids as anti-infective agents: opportunities and challenges.

Carboxylic organic acids are intermediates of central carbon metabolic pathways (e.g. acetic, propionic, citric, and lactic acid) long known to have potent antimicrobial potential, mainly at acidic pHs. The food industry has been leveraging those properties for years, using many of these acids as preservatives to inhibit the growth of pathogenic and/or spoilage fungal and bacterial species. A few of these molecules (the most prominent being acetic acid) have been used as antiseptics since Hippocratic medicine, mainly to treat infected wounds in patients with burns. With the growth of antibiotic therapy, the use of carboxylic acids (and other chemical antiseptics) in clinical settings lost relevance; however, with the continuous emergence of multi-antibiotic/antifungal resistant strains, the search for alternatives has intensified. This prospective article raises awareness of the potential of carboxylic acids to control infections in clinical settings, considering not only their previous exploitation in this context (which we overview) but also the positive experience of their safe use in food preservation. At a time of great concern with antimicrobial resistance and the slow arrival of new antimicrobial therapeutics to the market, further exploration of organic acids as anti-infective molecules may pave the way to more sustainable prophylactic and therapeutic approaches.

Structural role of K224 in taniborbactam inhibition of NDM-1.

Taniborbactam (TAN; VNRX-5133) is a novel bicyclic boronic acid ß-lactamase inhibitor (BLI) being developed in combination with cefepime (FEP). TAN inhibits both serine and some metallo-ß-lactamases. Previously, the substitution R228L in VIM-24 was shown to increase activity against oxyimino-cephalosporins like FEP and ceftazidime (CAZ). We hypothesized that substitutions at K224, the homologous position in NDM-1, could impact FEP/TAN resistance. To evaluate this, a library of codon-optimized NDM K224X clones for minimum inhibitory concentration (MIC) measurements was constructed; steady-state kinetics and molecular docking simulations were next performed. Surprisingly, our investigation revealed that the addition of TAN restored FEP susceptibility only for NDM-1, as the MICs for the other 19 K224X variants remained comparable to those of FEP alone. Moreover, compared to NDM-1, all K224X variants displayed significantly lower MICs for imipenem, tebipenem, and cefiderocol (32-, 133-, and 33-fold lower, respectively). In contrast, susceptibility to CAZ was mostly unaffected. Kinetic assays with the K224I variant, the only variant with hydrolytic activity to FEP comparable to NDM-1, confirmed that the inhibitory capacity of TAN was modestly compromised (IC50 0.01 µM vs 0.14 µM for NDM-1). Lastly, structural modeling and docking simulations of TAN in NDM-1 and in the K224I variant revealed that the hydrogen bond between TAN's carboxylate with K224 is essential for the productive binding of TAN to the NDM-1 active site. In addition to the report of NDM-9 (E149K) as FEP/TAN resistant, this study demonstrates the fundamental role of single amino acid substitutions in the inhibition of NDM-1 by TAN.

Design and synthesis of novel dithiazole carboxylic acid Derivatives: In vivo and in silico investigation of their Anti-Inflammatory and analgesic effects.

Inflammation is a complex set of interactions that can occur in tissues as the body's defensive response to infections, trauma, allergens, or toxic compounds. Therefore, in almost all diseases, it can be observed because of primary or secondary reasons. Since it is important to control and even eliminate the symptoms of inflammation in the treatment of many diseases, anti-inflammatory and analgesic drugs are always needed in the clinic. Therefore, the discovery of new anti-inflammatory/analgesic drugs with increased effectiveness and safer side effect profiles is among the popular topics of medicinal chemistry. Therefore, in this study, in order to synthesize and diversify new molecules, we focused on the N,N-dithiazole carboxylic acid core and linked it with the chalcone functional group. The final eleven molecules were analyzed via HRMS, 1H NMR, and 13C NMR. The antinociceptive effects of the test compounds were examined by tail-clip, hot-plate, and formalin methods in mice, while their anti-inflammatory activities were investigated by carrageenan-induced inflammation tests in rats. The motor activities of the experimental animals were evaluated using an activity-meter device. Obtained findings revealed that none of the test compounds (10 mg/kg) were effective in the tail-clip and hot-plate tests. However, compounds 4b, 4c, 4f, 4 h, and 4 k in the serial shortened the paw-licking times of mice in the late phase of the formalin test indicating that these compounds had peripherally-mediated antinociceptive effects. The same compounds, moreover, showed potent anti-inflammatory effects by significantly reducing paw edema of rats in the inflammation tests. To provide an approach to pharmacological findings regarding possible mechanisms of action, the binding modes of the most active compounds were investigated by in silico approaches. The results of molecular docking studies indicated that the anti-inflammatory and analgesic activities of the compounds might be related to the inhibition of both COX-1 and COX-2 isoenzymes. Findings obtained from in silico studies showed that 4 k, which was chosen as a model for its analogs in the series, forms strong bindings to the basic residues (Arg120, Tyr355), side pocket loop area and deep hydrophobic regions of the enzyme. Moreover, results of the molecular dynamics simulation studies revealed that ligand-COX enzyme complexes are quite stable. Obtained results of in vivo and in silico studies are in harmony, and all together point out that compounds 4b, 4c, 4f, 4 h, and 4 k have significant anti-inflammatory and analgesic activities with good ADME profiles. The potential of the derivatives, whose pharmacological activities were revealed for the first time in this study, as anti-inflammatory and analgesic drug candidates, needs to be evaluated through comprehensive clinical studies.

Carboxylic acid derivatives suppress the growth of Aspergillus flavus through the inhibition of fungal alpha-amylase.

Aspergillus favus (A. flavus) is a saprophytic fungus and a pathogen affecting several important foods and crops, including maize. A. flavus produces a toxic secondary metabolite called aflatoxin. Alpha-amylase (α-amylase), a hydrolytic enzyme produced by A. Flavus helps in the production of aflatoxin by hydrolysing the starch molecules in to simple sugars such as glucose and maltose. These simple sugars induce the production of aflatoxin. Inhibition of α-amylase has been proven as a potential way to reduce the production of aflatoxin. In the present study, we investigated the effect of selected carboxylic acid derivatives such as cinnamic acid (CA), 2, 4-dichlorophenoxyacetic acid (2,4-D), and 3-(4-hydroxyphenyl)-propionic acid (3,4-HPPA) on the fungal growth and for the α-amylase inhibitory activity. The binding potentials of these compounds with α-amylase have been confirmed by enzyme kinetics and isothermal titration calorimetry. Molecular docking and MD simulation studies were also performed to deduce the atomic level interaction between the protein and selected ligands. The results indicated that CA, 2,4-D and 3,4-HPPA can inhibit the fungal growth which could be partly due to the inhibition on fungal α-amylase activity.Communicated by Ramaswamy H. Sarma.

1,2,3-Triazole-based esters and carboxylic acids as nonclassical carbonic anhydrase inhibitors capable of cathepsin B inhibition.

Herein, we report the design and synthesis of a library of 28 new 1,2,3-triazole derivatives bearing carboxylic acid and ester moieties as dual inhibitors of carbonic anhydrase (CA) and cathepsin B enzymes. The synthesised compounds were assayed in vitro for their inhibition potential against four human CA (hCA) isoforms, I, II, IX and XII. The carboxylic acid derivatives displayed low micromolar inhibition against hCA II, IX and XII in contrast to the ester derivatives. Most of the target compounds showed poor inhibition against the hCA I isoform. 4-Fluorophenyl appended carboxylic acid derivative 6c was found to be the most potent inhibitor of hCA IX and hCA XII with a KI value of 0.7 µM for both the isoforms. The newly synthesised compounds showed dual inhibition towards CA as well as cathepsin B. The ester derivatives exhibited higher % inhibition at 10-7 M concentration as compared with the corresponding carboxylic acid derivatives against cathepsin B. The results from in silico studies of the target compounds with the active site of cathepsin B were found in good correlation with the in vitro results. Moreover, two compounds, 5i and 6c, showed cytotoxic activity against A549 lung cancer cells, with IC50 values lower than 100 µM.

Relative inhibitory activities of the broad-spectrum ß-lactamase inhibitor taniborbactam against metallo-ß-lactamases.

Taniborbactam (TAN) is a novel broad-spectrum ß-lactamase inhibitor with significant activity against subclass B1 metallo-ß-lactamases (MBLs). Here, we showed that TAN exhibited an overall excellent activity against B1 MBLs including most NDM- and VIM-like as well as SPM-1, GIM-1, and DIM-1 enzymes, but not against SIM-1. Noteworthy, VIM-1-like enzymes (particularly VIM-83) were less inhibited by TAN than VIM-2-like. Like NDM-9, NDM-30 (also differing from NDM-1 by a single amino acid substitution) was resistant to TAN.

New Indole-6-Carboxylic Acid Derivatives as Multi-Target Antiproliferative Agents: Synthesis, in Silico Studies, and Cytotoxicity Evaluation.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are commonly overexpressed in cancers making them appealing targets for cancer therapeutics. Two groups of indole-6-carboxylic acid derivatives, hydrazone derivatives targeting EGFR and oxadiazole derivatives targeting VEGFR-2, were synthesized and characterized using FT-IR, 1 H-NMR, 13 CNMR, and HR-MS techniques. Binding patterns to potential molecular targets were studied using molecular docking and compared to standard EGFR and VEGFR-2 inhibitors. The newly synthesized compounds were cytotoxic to the three cancer cell lines tested (HCT-116, HeLa, and HT-29 cell lines) as evaluated by the MTT assay. Compound 3 b (EGFR-targeting) and compound 6 e (VEGFR-2-targeting) possessed the highest antiproliferation activity, were cancer-selective, arrested cancer cells in the G2/M phase, induced the extrinsic apoptosis pathway, and had the highest EGFR/VEGFR-2 enzyme inhibitory activity, respectively. The structure-activity relationships of the new compounds showed that the presence of an aryl or heteroaryl fragment attached to a linker is required for the anti-tumor activity. In conclusion, the findings of the current study suggest that compounds 3 b and 6 e are promising cytotoxic agents that act by inhibiting EGFR and VEGFR-2 tyrosine kinases, respectively.

Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors.

Urate transporter 1 (URAT1) is a clinically validated target for the treatment of hyperuricemia and gout. Due to the absence of protein structures, the molecular design of new URAT1 inhibitors generally resorts to ligand-based approaches. Two series of biphenyl carboxylic acids were designed based on the structures of URAT1 inhibitors Epaminurad and Telmisartan via a strategy of pharmacophore fusion. Fifty-one novel compounds were synthesized and most of them showed obvious inhibition against human URAT1. A1 and B21 were identified as the most potent URAT1 inhibitors in series A and B, respectively. They exhibited IC50 values of 0.93 µM and 0.17 µM, which were comparable or superior to the clinical uricosuric drug benzbromarone. The results confirmed the effectiveness of ligand-based approaches in identifying novel and potent URAT1 inhibitors.

Synthesis, Cytotoxic Activity and In Silico Study of Novel Dihydropyridine Carboxylic Acids Derivatives.

To aid the possible prevention of multidrug resistance in tumors and cause lower toxicity, a set of sixteen novel dihydropyridine carboxylic acids derivatives 3a-p were produced; thus, the activation of various ynones with triflic anhydride was performed, involving a nucleophilic addition of several bis(trimethylsilyl) ketene acetals, achieving good yields requiring easy workup. The target molecules were unequivocally characterized by common spectroscopic methods. In addition, two of the tested compounds (3a, and 3b) were selected to perform in silico studies due to the highest cytotoxic activity towards the HCT-15 cell line (7.94 ± 1.6 µM and 9.24 ± 0.9 µM, respectively). Employing theoretical calculations with density functional theory (DFT) using the B3LYP/6-311++G(d,p) showed that the molecular parameters correlate adequately with the experimental results. In contrast, predictions employing Osiris Property Explorer showed that compounds 3a and 3b present physicochemical characteristics that would likely make it an orally active drug. Moreover, the performance of Docking studies with proteins related to the apoptosis pathway allowed a proposal of which compounds could interact with PARP-1 protein. Pondering the obtained results (synthesis, in silico, and cytotoxic activity) of the target compounds, they can be judged as suitable antineoplastic agent candidates.

Mycobacterium tuberculosis Inhibitors Based on Arylated Quinoline Carboxylic Acid Backbones with Anti-Mtb Gyrase Activity.

New antitubercular agents with either a novel mode of action or novel mode of inhibition are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new arylated quinoline carboxylic acids (QCAs) having activity against replicating and non-replicating Mycobacterium tuberculosis (Mtb), the causative agent of TB. Thus, the synthesis, characterization, and in vitro screening (MABA and LORA) of 48 QCAs modified with alkyl, aryl, alkoxy, halogens, and nitro groups in the quinoline ring led to the discovery of two QCA derivatives, 7i and 7m, adorned with C-2 2-(naphthalen-2-yl)/C-6 1-butyl and C-2 22-(phenanthren-3-yl)/C-6 isopropyl, respectively, as the best Mtb inhibitors. DNA gyrase inhibition was shown to be exhibited by both, with QCA 7m illustrating better activity up to a 1 µM test concentration. Finally, a docking model for both compounds with Mtb DNA gyrase was developed, and it showed a good correlation with in vitro results.

Identification of 5-[5-cyano-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamido] thiazole-4-carboxylic acid as a promising dual inhibitor of urate transporter 1 and xanthine oxidase.

In combination with allopurinol, tranilast is used as an urate transporter 1 (URAT1) inhibitor for the treatment of hyperuricemia, but its structure-activity relationship concerning URAT1 inhibitory activity is rarely studied. In this paper, analogs 1-30 were designed and synthesized using scaffold hopping strategy on the basis of tranilast and the privileged scaffold indole. Then, URAT1 activity was evaluated using 14C-uric acid uptake assay with HEK293-URAT1 overexpressing cells. Compared with tranilast (inhibitory rate = 44.9% at 10 µM), most compounds displayed apparent inhibitory effects, ranging from 40.0% to 81.0% at 10 µM on URAT1. Surprisingly, along with the bringing in of a cyano group at the 5-position of indole ring, compounds 26 and 28-30 exerted xanthine oxidase (XO) inhibitory activity. In particular, compound 29 presented potency on URAT1 (48.0% at 10 µM) and XO (IC50 = 1.01 µM). Molecular simulation analysis revealed that the basic structure of compound 29 had an affinity with URAT1, and XO. Furthermore, compound 29 demonstrated a significant hypouricemic effect in a potassium oxonate-induced hyperuricemia rat model at an oral dose of 10 mg/kg during in vivo tests. In summary, tranilast analog 29 was identified as a potent dual-target inhibitor of URAT1 and XO, and a promising lead compound for further investigation.