Dissociation Constant Research Articles

Toxicological and Pharmacological Activities, and Potential Medical Applications, of Marine Algal Toxins.

Marine algal toxins have garnered significant attention in the research community for their unique biochemical properties and potential medical applications. These bioactive compounds, produced by microalgae, pose significant risks due to their high toxicity, yet offer promising therapeutic benefits. Despite extensive research identifying over 300 marine algal toxins, including azaspiracids, brevetoxins, cyclic imines, and yessotoxins, gaps remain in the understanding of their pharmacological potential. In this paper, we critically review the classification, bioactive components, toxicology, pharmacological activities, and mechanisms of these toxins, with a particular focus on their clinical applications. Our motivation stems from the increasing interest in marine algal toxins as candidates for drug development, driven by their high specificity and affinity for various biological receptors. We aim to bridge the gap between toxicological research and therapeutic application, offering insights into the advantages and limitations of these compounds in comparison to other bioactive substances. This review not only enhances the understanding of marine algal toxins' complexity and diversity, but also highlights their extensive application potential in medicine and bioscience, providing a foundation for future research and development in this field.

In Vitro and In Silico Analysis of PTP1B Inhibitors from Cleistocalyx operculatus Leaves and Their Effect on Glucose Uptake.

As part of our ongoing research on new anti-diabetic compounds from ethnopharmacologically consumed plants, two previously undescribed lupane-type triterpenoids (1 and 2) with dicarboxylic groups, an undescribed nor-taraxastane-type triterpenoid (3), and 14 known compounds (4-17) were isolated from the leaves of Cleistocalyx operculatus. Extensive spectroscopic analysis (IR, HRESIMS, 1D, and 2D NMR) was used for structure elucidation, while the known compounds were compared to reference data reported in the scientific literature. All the isolates (1-17) were evaluated for their inhibitory effects on the protein tyrosine phosphatase 1B (PTP1B) enzyme. Compounds 6, 9, and 17 showed strong PTP1B inhibitory activities. The mechanism of PTP1B inhibition was studied through enzyme kinetic experiments. A non-competitive mechanism of inhibition was determined using Lineweaver-Burk plots for compounds 6, 9, and 17. Additionally, Dixon plots were employed to determine the inhibition constant. Further insights were gained through a structure-activity relationship study and molecular docking analysis of isolated compounds with the PTP1B crystal structure. Moreover, all isolates (1-17) were tested for their stimulatory effects on the uptake of 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl) amino]-D-glucose (2-NBDG) in differentiated 3T3-L1 adipocyte cells. Compounds 6, 13, and 17 exhibited strong glucose absorption stimulation activity in a dose-dependent manner.

Inhibition of Yeast Hexokinase by Acyl Glucosides of Phloretin and its Implication in the Warburg Effect

AbstractContrary to differentiated cells, cancer cells predominantly convert glucose to lactate even under conditions of adequate oxygen supply (“Warburg effect”). The initial enzyme implicated in this route is hexokinase, which transforms D‐glucose into D‐glucose‐6‐phosphate. We proposed the use of different polyphenols (resveratrol, epigallocatechin gallate, pterostilbene, phloretin) and their derivatives (α‐glucosides and acylated α‐glucosides) to inhibit this enzyme. For this study, we used Saccharomyces cerevisiae hexokinase, whose two isoforms show high resemblance at the active site with human hexokinase HK2. To monitor the reactions, a method of anion‐exchange chromatography coupled with pulsed amperometric detection (HPAEC‐PAD) was developed. Remarkably, most of the assayed compounds inhibited the enzyme more than 50 % in the standard assay. Among them, phloretin 4’‐O‐(6’’‐O‐octanoyl)‐α‐D‐glucopyranoside showed the highest inhibition and was studied in depth to determine the inhibition pattern and inhibition constant. The Ki for glucose was calculated to be 22.1±0.4 μM. Computational models of inhibition were carried out with the three molecules displaying the highest inhibition, and correlated adequately with the observed inhibitory effects on the enzyme. The inhibitory effect of several of the assayed polyphenols on hexokinase and their lack of toxicity renders them promising candidates as adjuvant drugs for cancer therapy.

Reductive samarium (electro)catalysis enabled by SmIII-alkoxide protonolysis.

Samarium diiodide (SmI2) is a privileged, single-electron reductant deployed in diverse synthetic settings. However, generalizable methods for catalytic turnover remain elusive because of the well-known challenge associated with cleaving strong SmIII-O bonds. Prior efforts have focused on the use of highly reactive oxophiles to enable catalyst turnover. However, such approaches give rise to complex catalyst speciation and intrinsically limit the synthetic scope. Herein, we leveraged a mild and selective protonolysis strategy to achieve samarium-catalyzed, intermolecular reductive cross-coupling of ketones and acrylates with broad scope. The modularity of our approach allows rational control of selectivity based on solvent, pKa (where Ka is the acid dissociation constant), and the samarium coordination sphere and provides a basis for future developments in catalytic and electrocatalytic lanthanide chemistry.

Hypotensive effect of potent angiotensin-I-converting enzyme inhibitory peptides from corn gluten meal hydrolysate: Gastrointestinal digestion and transepithelial transportation modifications

The study examined the antihypertensive effect of peptides derived from pepsin-hydrolyzed corn gluten meal, namely KQLLGY and PPYPW, and their in silico gastrointestinal tract digested fragments, KQL and PPY, respectively. KQLLGY and PPYPW showed higher angiotensin I-converting enzyme (ACE)-inhibitory activity and lower ACE inhibition constant (Ki) values when compared to KQL and PPY. Only KQL showed a mild antihypertensive effect in spontaneously hypertensive rats with −7.83 and − 5.71 mmHg systolic and diastolic blood pressure values, respectively, after 8 h oral administration. During passage through Caco-2 cells, KQL was further degraded to QL, which had reduced ACE inhibitory activity. In addition, molecular dynamics revealed that the QL-ACE complex was less stable compared to the KQL-ACE. This study reveals that structural transformation during peptide permeation plays a vital role in attenuating antihypertensive effect of the ACE inhibitor peptide.

Engineering aptamers to enhance their interaction with protein target for selective inhibition of cell surface receptors

Cell surface receptors play a key role in intracellular signaling, and their overexpression and activation are among the drivers of multiple diseases. Selective inhibition of cell surface receptors is important for regulating intracellular signaling pathways and cell behavior. Here, we design engineered aptamers to selectively inhibit receptor function. In this strategy, the aptamer specifically recognizing the extracellular structural domain of the EGFR, was conjugated to an adamantane moiety through linking arms of various lengths in order to obtain better performances toward EGFR. These interactions inhibit EGFR dimerization, thereby impeding the activation of downstream signaling pathways. It is shown that the adamantane-modified aptamers exhibit superior inhibition of downstream effector proteins relative to the unmodified aptamers. The optimal inhibitory effect was observed with a linker arm of 40 T-base in length. Notably, the best-performing adamantane-modified aptamer specifically binds to A549 cells with a dissociation constant (22.6 ± 4.5 nM) that is approximately 4-fold lower than that of the parent EGFR aptamer (94.4 ± 21.9 nM). We further combine the use of the adamantane-modified aptamer with that of genistein, a natural isoflavone compound with EGFR tyrosine kinase inhibition activity, to enhance the inhibitory effect on EGFR and its downstream signaling employing a synergistic action. This study is expected to provide a versatile approach for the improvement of existing aptamers obtaining increased selective inhibition of cell surface receptors.

Dual 5-HT2A and 5-HT2C Receptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis.

Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson's disease psychosis, pimavanserin (1), a 5-HT2A receptor inverse agonist having minimal 5-HT2C receptor affinity and no dopamine D2 receptor affinity, was approved in the United States, but not for dementia-related psychosis due to limited efficacy issues. Herein, we report on the identification of a potent and dual 5-HT2A and 5-HT2C receptor inverse agonist 8 having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT2A and 5-HT2C receptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT2A and 5-HT2C occupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT2C affinity in 1 followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8 that showed significant antipsychotic efficacy due to the involvement of both receptors.

Interaction of Purine and its Derivatives with A1, A2-Adenosine Receptors and Vascular Endothelial Growth Factor Receptor-1 (Vegf-R1) as a Therapeutic Alternative to Treat Cancer.

There are several studies that indicate that cancer development may be conditioned by the activation of some biological systems that involve the interaction of different biomolecules, such as adenosine and vascular endothelial growth factor. These biomolecules have been targeted of some drugs for treat of cancer; however, there is little information on the interaction of purine derivatives with adenosine and vascular endothelial growth factor receptor (VEGF-R1). The aim of this research was to determine the possible interaction of purine (1: ) and their derivatives (2-31: ) with A1, A2-adenosine receptors, and VEGF-R1. Theoretical interaction of purine and their derivatives with A1, A2-adenosine receptors and VEGF-R1 was carried out using the 5uen, 5mzj and 3hng proteins as theoretical tools. Besides, adenosine, cgs-15943, rolofylline, cvt-124, wrc-0571, luf-5834, cvt-6883, AZD-4635, cabozantinib, pazopanib, regorafenib, and sorafenib drugs were used as controls. The results showed differences in the number of aminoacid residues involved in the interaction of purine and their derivatives with 5uen, 5mzj and 3hng proteins compared with the controls. Besides, the inhibition constants (Ki) values for purine and their derivatives 5: , 9: , 10: , 14: , 15: , 16: , and 20: were lower compared with the controls CONCLUSIONS: Theoretical data suggest that purine and their derivatives 5: , 9: , 10: , 14: , 15: , 16: , and 20: could produce changes in cancer cell growth through inhibition of A1, A2-adenosine receptors and VEGFR-1 inhibition. These data indicate that these purine derivatives could be a therapeutic alternative to treat some types of cancer.

ML335 inhibits TWIK2 channel-mediated potassium efflux and attenuates mitochondrial damage in MSU crystal-induced inflammation

BackgroundActivation of the NLRP3 inflammasome is critical in the inflammatory response to gout. Potassium ion (K+) efflux mediated by the TWIK2 channel is an important upstream mechanism for NLRP3 inflammasome activation. Therefore, the TWIK2 channel may be a promising therapeutic target for MSU crystal-induced inflammation. In the present study, we investigated the effect of ML335, a known K2P channel modulator, on MSU crystal-induced inflammatory responses and its underlying molecular mechanisms.MethodsBy molecular docking, we calculated the binding energies and inhibition constants of five K2P channel modulators (Hydroxychloroquine, Fluoxetine, DCPIB, ML365 and ML335) with TWIK2. Intracellular potassium ion concentration and mitochondrial function were assessed by flow cytometry. The interaction between MARCH5 and SIRT3 was demonstrated by immunoprecipitation and Western blotting assay. MSU suspensions were injected into mouse paw and peritoneal cavity to induce acute gout model.ResultsML335 has the highest binding energy and the lowest inhibition constant with TWIK2 in the five calculated K2P channel modulators. In comparison, among these five compounds, ML335 efficiently inhibited the release of IL-1β from MSU crystal-treated BMDMs. ML335 decreased MSU crystal-induced K+ efflux mainly dependent on TWIK2 channel. More importantly, ML335 can effectively inhibit the expression of the mitochondrial E3 ubiquitin ligase MARCH5 induced by MSU crystals, and MARCH5 can interact with the SIRT3 protein. ML335 blocked MSU crystal-induced ubiquitination of SIRT3 protein by MARCH5. In addition, ML335 improved mitochondrial dynamics homeostasis and mitochondrial function by inhibiting MARCH5 protein expression. ML335 attenuated the inflammatory response induced by MSU crystals in vivo and in vitro.ConclusionInhibition of TWIK2-mediated K+ efflux by ML335 alleviated mitochondrial injury via suppressing March5 expression, suggesting that ML335 may be an effective candidate for the future treatment of gout.

Spectroscopic and solution properties characterization of quaternary ammonium ion containing polycations complexed with fluorescent rhodamine sulfonic acid dyes

Based on the growing range of applications for polycations in research and commercial materials, a continuing need exists to advance the fundamental knowledge and understanding of this class of materials. Spectroscopic and solution properties characterizations of noncovalently labeled, fluorescent Alexa Fluor® dye complexes of two commercial polycations, poly(2-(trimethylamino) ethyl methacrylate) monocation and poly[bis[2-chloroethyl] ether-alt-1,3-bis[3-(dimethylamino) propyl] urea] dication are reported to help address this need. A variety of fluorescence spectroscopic methods are used with a special emphasis on fluorescence correlation spectroscopy (FCS) which is applied to characterize the Stokes radius (RS) and equilibrium dissociation constants (Kd) of dye-polycation complexes at nanomolar dye concentrations. Resulting RS values indicate dye binding to individual polycation chains. Measured Kd values in the sub-micromolar range are consistent with strong dye binding. Increasing solution ionic strength with sodium chloride addition inhibits dye binding and decreases the RS of dye-polycation complexes due to size collapse of polycation chains. The complexes differ in their solution stability to ionic strength changes suggesting that both electrostatic and hydrophobic binding interactions influence dye binding. This study establishes the viability of noncovalent dye-polycation complexation in concert with FCS characterization as a general approach for investigating the properties of quaternary ammonium ion containing polycations in aqueous solution.

Repurposing Duloxetine as a Potent Butyrylcholinesterase Inhibitor: Potential Cholinergic Enhancing Benefits for Elderly Individuals with Depression and Cognitive Impairment.

Despite the advent of new treatment strategies, cholinesterase inhibitors (ChEIs) are still the go-to treatment for dementia disorders. ChEIs act by inhibiting the main acetylcholine-degrading enzyme, acetylcholinesterase (AChE). Nonetheless, accumulating evidence indicates that the impact of inhibition of the sister enzyme, butyrylcholinesterase (BChE), could be even broader in older adults due to the multifaceted role of BChE in several biological functional pathways. Therefore, we employed an in silico modeling-based drug repurposing strategy to identify novel potent BChE inhibitors from the FDA drug database. This was followed by in vitro screening and ex vivo enzyme kinetic validation using human plasma samples as the source of BChE. The analysis revealed that the antidepressant drug, duloxetine, inhibited BChE with high selectivity in comparison to AChE. In contrast, two other antidepressants, namely, citalopram and escitalopram exhibited a weak to moderate activity. Ex vivo enzyme inhibition kinetic analyses indicated that duloxetine acted as a competitive inhibitor of BChE with an inhibition constant (K i) of 210 nM. This K i value is comparable with 100-400 nM concentration of duloxetine following normal dosages in humans, thereby indicating that duloxetine should be able to induce a pharmacologically and biologically relevant in vivo inhibition of BChE. Additionally, we performed the enzyme inhibition kinetic assessment in parallel for ethopropazine, a known potent selective BChE inhibitor, and physostigmine, a dual inhibitor of AChE and BChE. These analyses indicated that duloxetine should be considered a potent BChE inhibitor since its K i was comparable with ethopropazine (K i = 150 nM) but was 4 times smaller than that of physostigmine (K i = 840 nM). In conclusion, this study reports the discovery of duloxetine being a highly potent selective competitive BChE inhibitor. This, in turn, indicates that duloxetine could be the choice of antidepressive treatment in older adults with both depressive and dementia symptoms since it may offer additional clinically beneficial effects via this secondary mode of cholinergic enhancing action.

Optimized methods for measuring competitive binding of chemical substances to thyroid hormone distributor proteins transthyretin and thyroxine binding globulin

Transthyretin (TTR) and thyroxine-binding globulin (TBG) are two major thyroid hormone (TH) distributor proteins in human plasma, playing important roles in stabilizing the TH levels in plasma, delivery of TH to target tissues, and trans-barrier transport. Binding of xenobiotics to these distributor proteins can potentially affect all these three important roles of distributor proteins. Therefore, fast and cost-effective experimental methods are required for both TTR and TBG to screen both existing and new chemicals for their potential binding. In the present study, the TTR-binding assay was therefore simplified, optimized and pre-validated, while a new TBG-binding assay was developed based on fluorescence polarization as a readout. Seven model compounds (including positive and negative controls) were tested in the pre-validation study of the optimized TTR-binding assay and in the newly developed TBG-binding assay. The dissociation constants of the natural ligand (thyroxine, T4) and potential competitors were determined and compared between two distributor proteins, showing striking differences for perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA).

Kinetics studies and effect of the process parameters on the biodegradation of methyl orange dye

The biodegradation of methyl orange dye using Stenotrophomonas maltophilia (HE963840.1) bacteria was studied. The optimization of the biodegradation process has been performed using central composite design (CCD) of response surface methodology (RSM) with respect to three parameters namely temperature, initial dye concentration and inoculum dose. The response is best described by the second order polynomial with R2 value of 0.99. The optimized values of the process parameters were empirically checked and the model equation of the RSM was found statistically significant. The errors between experimental and model predicted results were found to be less than 8 %. The maximum dye removal efficiency was found as 86.5 ± 0.1 %. The growth kinetics of the bacteria was also studied and it is best described by Andrew-Haldane model. The values of kinetic parameters maximum specific growth rate (μmax), inhibition constant (KI) and saturation constant (KS) were found as 0.032 h−1, 156 mg/L and 78 mg/L respectively.

Development of a novel sandwich immunoassay based on targeting recombinant Francisella outer membrane protein A for the diagnosis of tularemia.

Tularemia, caused by the bacterium Francisella tularensis, poses health risks to humans and can spread through a variety of routes. It has also been classified as a Tier 1 Select agent by the CDC, highlighting its potential as a bioterrorism agent. Moreover, it is difficult to diagnose in a timely fashion, owing to the non-specific nature of tularemia infections. Rapid, sensitive, and accurate detection methods are required to reduce mortality rates. We aimed to develop antibodies directed against the outer membrane protein A of F. tularensis (FopA) for rapid and accurate diagnosis of tularemia. We used a baculovirus insect cell expression vector system to produce the FopA antigen and generate anti-FopA antibodies through immunization of BALB/c mice. We then employed hybridoma and phage display technologies to screen for antibodies that could recognize unique epitopes on FopA. Two monoclonal antibodies, 6B12 and 3C1, identified through phage display screening specifically bound to recombinant FopA in a dose-dependent manner. The binding affinity of the anti-FopA 6B12 and 3C1 antibodies was observed to have an equilibrium dissociation constant of 1.76 × 10-10 M and 1.32 × 10-9 M, respectively. These antibodies were used to develop a sandwich ELISA system for the diagnosis of tularemia. This assay was found to be highly specific and sensitive, with detection limits ranging from 0.062 ng/mL in PBS to 0.064 ng/mL in skim milk matrices. Our findings demonstrate the feasibility of a novel diagnostic approach for detecting F. tularensis based on targeting FopA, as opposed to existing tests that target the bacterial lipopolysaccharide.

Optimization of a Modular Nanotransporter Design for Targeted Intracellular Delivery of Photosensitizer.

Modular nanotransporters (MNTs) are drug delivery systems for targeted cancer treatment. As MNTs are composed of several modules, they offer the advantage of high specificity and biocompatibility in delivering drugs to the target compartment of cancer cells. The large carrier module brings together functioning MNT modules and serves as a platform for drug attachment. The development of smaller-sized MNTs via truncation of the carrier module appears advantageous in facilitating tissue penetration. In this study, two new MNTs with a truncated carrier module containing either an N-terminal (MNTN) or a C-terminal (MNTC) part were developed by genetic engineering. Both new MNTs demonstrated a high affinity for target receptors, as revealed by fluorescent-labeled ligand-competitive binding. The liposome leakage assay proved the endosomolytic activity of MNTs. Binding to the importin heterodimer of each truncated MNT was revealed by a thermophoresis assay, while only MNTN possessed binding to Keap1. Finally, the photodynamic efficacy of the photosensitizer attached to MNTN was significantly higher than when attached to either MNTC or the original MNTs. Thus, this work reveals that MNT's carrier module can be truncated without losing MNT functionality, favoring the N-terminal part of the carrier module due to its ability to bind Keap1.

A general model for prediction of the CO2 equilibrium solubility in aqueous tertiary amine systems

AbstractWe have developed a general model to predict CO2 equilibrium solubility in aqueous tertiary amine solutions by relating the equilibrium constant (K1) to all relevant parameters in a logical function form. Testing our model, we measured CO2 equilibrium solubility data for N‐methylmorpholine (NMM) and N‐ethylmorpholine (NEM) across various conditions. Comparison with six existing models reveals our general model's superior predictive performance not only for NMM and NEM but also for an additional 10 tertiary amine solutions from literature, indicating its universality. Comprehensively considering the CO2 equilibrium solubility, amine dissociation constant (pKa) and the CO2 absorption heat, it is found that NMM and NEM may be promising desorption promoters enabling to reduce the energy cost. In short, it is expected the general model can be applied to more other tertiary amine systems.

Single Chelator-Minibody Theranostic Agents for 89Zr PET Imaging and 177Lu Radiopharmaceutical Therapy of PSMA-Expressing Prostate Cancer.

Here we describe an anti-prostate-specific membrane antigen (PSMA) minibody (IAB2MA) conjugated to an octadentate, macrocyclic chelator based on four 1-hydroxypyridin-2-one coordinating units (Lumi804 [L804]) labeled with 89Zr (PET imaging) and 177Lu (radiopharmaceutical therapy), with the goal of developing safer and more efficacious treatment options for prostate cancer. Methods: L804 was compared with the current gold standard chelators, DOTA and deferoxamine (DFO), conjugated to IAB2MA for radiolabeling with 177Lu and 89Zr in cell binding, preclinical biodistribution, imaging, dosimetry, and efficacy studies in the PSMA-positive PC3-PIP tumor-bearing mouse model of prostate cancer. Results: Quantitative radiolabeling (>99% radiochemical yield) of L804-IAB2MA with 177Lu or 89Zr was achieved at ambient temperature in under 30 min, comparable to 89Zr labeling of DFO-IAB2MA. In contrast, DOTA-IAB2MA was radiolabeled with 177Lu for 30 min at 37°C in approximately 90% radiochemical yield, requiring further purification. Using europium(III) as a luminescent surrogate, high binding affinity of Eu-L804-IAB2MA to PSMA was demonstrated in PC3-PIP cells (dissociation constant, 4.6 ± 0.6 nM). All 4 radiolabeled constructs showed significantly higher levels of internalization after 30 min in the PC3-PIP cells than in PSMA-negative PC3-FLU cells. The accumulation of 177Lu- and 89Zr-L804-IAB2MA in PC3-PIP tumors and all organs examined (i.e., heart, liver, spleen, kidney, muscle, salivary glands, lacrimal glands, carcass, and bone) was significantly lower than that of 177Lu-DOTA-IAB2MA and 89Zr-DFO-IAB2MA at 96 and 72 h after injection, respectively. Generally, SPECT/CT and PET/CT imaging data showed no significant difference in the SUVmean of the tumors or muscle between the radiotracers. Dosimetry analysis via both organ-level and voxel-level dose calculation methods indicated significantly higher absorbed doses of 177Lu-DOTA-IAB2MA in tumors, kidney, liver, muscle, and spleen than of 177Lu-L804-IAB2MA. PC3-PIP tumor-bearing mice treated with single doses of 177Lu-L804-IAB2MA (18.4 or 22.2 MBq) exhibited significantly prolonged survival and reduced tumor volume compared with unlabeled minibody control. No significant difference in survival was observed between groups of mice treated with 177Lu-L804-IAB2MA or 177Lu-DOTA-IAB2MA (18.4 or 22.2 MBq). Treatment with 177Lu-L804-IAB2MA resulted in lower absorbed doses in tumors and less toxicity than that of 177Lu-DOTA-IAB2MA. Conclusion: 89Zr- and 177Lu-L804-IAB2MA may be a promising theranostic pair for imaging and therapy of prostate cancer.

Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity

The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of MtFolB. These compounds exhibited IC50 values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the M. tuberculosis H37Rv strain were evaluated. Compound 3e exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound 3e showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting MtFolB, an attractive molecular target for TB drug development.

Synthesis and biological evaluation of novel aminoquinolines with an n-octyl linker: Impact of halogen substituents on C(7) or a terminal amino group on anticholinesterase and BACE1 activity

Alzheimer’s disease is age-related multifactorial neurodegenerative disease manifested by gradual loss of memory, cognitive decline and changes in personality. Due to rapid and continuous growth of its prevalence, the treatment of Alzheimer’s disease calls for development of new and efficacies drugs, especially those that could be able to simultaneously act on more than one of possible targets of action. Aminoquinolines have proven to be a highly promising structural scaffold in the design of such a drug as cholinesterases and β-secretase 1 inhibitors. In this study, we synthesised twenty-two new 4-aminoquinolines with different halogen atom and its position in the terminal N-benzyl group or with a trifluoromethyl or a chlorine as C(7)-substituents on the quinoline moiety. All compounds were evaluated as multi-target-directedligands by determining their inhibition potency towards human acetylcholinesterase, butyrylcholinesterase and β-secretase 1. All of the tested derivatives were very potent inhibitors of human acetylcholinesterase and butyrylcholinesterase with inhibition constants (Ki) in the nM to low μM range. Most were estimated to be able to cross the blood–brain barrier by passive transport and were nontoxic toward cells that represented the main models of individual organs.

The enzyme kinetic studies, DNA protection and antioxidant activities of furan/ thiophene-2-carboxamide derivatives

Three furan and/or thiophene-2-carboxamide compounds, namely N-(furan-2-ylmethyl)thiophene-2-carboxamide (1), N-(furan-2-carbonyl)furan-2-carboxamide (2), and N-(Thiophene-2-ylmethyl)furan-2-carboxamide (3) were investigated the enzyme kinetic studies by urease, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). The inhibition constant (Ki) of Compound (CPD)3 by AChE was determined as 0.10 mM, and the Ki value by BChE was determined as 0.07 mM. In comparison, the Ki value of CPD1 by urease was determined as 0.10 mM. These CPDs were examined for antioxidant activity by the DPPH˙ scavenging method. CPD3 exhibited 98.93% DPPH scavenging activity compared to ascorbic acid, the positive control group. Furthermore, the DNA-protective activities of the compounds were investigated, and the DNA protection activity of CPD1 was observed to be 78%. The findings suggest that thiophene/furan carboxy amide-containing CPD1 and CPD3 might be exploited as potential structures for evaluating pharmaceuticals with greater potency.