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• A mechanism-based hybrid model, coupling target-mediated drug disposition and a minimal model of the renin-angiotensin system, was developed to characterize the pharmacokinetic and pharmacodynamic properties of enalaprilat, administered as the prodrug enalapril, in humans. • Model-based simulations of the final model predicted about a 6- to 7-fold shift in the enalaprilat ex vivo potency from its in vivo binding affinity, which is consistent with both observations and theoretical expectations of pharmacological antagonists that exhibit target-mediated drug disposition (TMDD). • Empirical functions based on operational models of agonism/antagonism were also derived that similarly suggest a role of drug, angiotensin, and total receptor concentration in the shift in enalaprilat ex vivo potency from in vivo binding affinity. Drug effects are often assumed to be directly proportional to the fraction of occupied targets. However, for a number of antagonists that exhibit target-mediated drug disposition (TMDD), such as angiotensin-converting enzyme (ACE) inhibitors, drug binding to the target at low concentrations may be significant enough to influence pharmacokinetics but insufficient to elicit a drug response (i.e., differences in drug-target binding affinity and potency). In this study, a pharmacokinetic/pharmacodynamic model for enalaprilat was developed in humans to provide a theoretical framework for assessing the relationship between ex vivo drug potency (IC 50) and in vivo target - binding affinity (K D). The model includes competitive binding of angiotensin I and enalaprilat to ACE and accounts for the circulating target pool. Data were obtained from the literature, and model fitting and parameter estimation were conducted using maximum likelihood in ADAPT5. The model adequately characterized time-courses of enalaprilat concentrations and four biomarkers in the renin-angiotensin system and provided estimates for in vivo K D (0.646 nM) and system-specific parameters, such as total target density (32.0 nM) and fraction of circulating target (19.8%), which were in agreement with previous reports. Model simulations were used to predict the concentration-effect curve of enalaprilat, revealing a 6.3-fold increase in IC 50 from K D. Additional simulations demonstrated that target reserve and degradation parameters are key factors determining the extent of shift of enalaprilat ex vivo potency from its in vivo binding affinity. This may be a common phenomenon for drugs exhibiting TMDD and has implications for translating binding affinity to potency in drug development. [ABSTRACT FROM AUTHOR]

All known organisms encode 20 canonical amino acids by base triplets in the genetic code. The cellular translational machinery produces proteins consisting mainly of these amino acids. Several hundred natural amino acids serve important functions in metabolism, as scaffold molecules, and in signal transduction. New side chains are generated mainly by post-translational modifications, while others have altered backbones, such as the β- or γ-amino acids, or they undergo stereochemical inversion, e.g., in the case of D-amino acids. In addition, the number of non-canonical amino acids has further increased by chemical syntheses. Since many of these non-canonical amino acids confer resistance to proteolytic degradation, they are potential protease inhibitors and tools for specificity profiling studies in substrate optimization and enzyme inhibition. Other applications include in vitro and in vivo studies of enzyme kinetics, molecular interactions and bioimaging, to name a few. Amino acids with bio-orthogonal labels are particularly attractive, enabling various cross-link and click reactions for structure-functional studies. Here, we cover the latest developments in protease research with non-canonical amino acids, which opens up a great potential, e.g., for novel prodrugs activated by proteases or for other pharmaceutical compounds, some of which have already reached the clinical trial stage. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is among the most common malignancy and the third prime cause of cancer-associated mortalities. Long-term inflammation of the colon can promote carcinogenesis by facilitating oxidative stress which enhances deoxyribonucleic acid damage resulting in the tumor initiation step. The existing chemotherapeutic options are often associated with adverse reactions and emergence of drug resistance. The carefully selected plants are cited to demonstrate anticancer properties as has been revealed in this review. Of significance, these plant species are widely available, especially in Africa Objective: The major goal was to present an updated comprehensive review of herbal plants used to treat colon cancer around the world. More specifically, the goal of this study was to analyse a group of selected plant species with proven efficacy, safety, and pharmacological effects on colon cancer models for further research. Methods: A systematic search of relevant literature was performed considering all the articles published until November 2021 through searching six library databases and a web search engine, Google scholar. It was created using MeSH terms and free text describing plant species and colorectal cancer. For subsequent investigation, all articles describing the use of medicinal plants to treat colorectal cancer and/or their pharmacological evaluation were maintained. The plant species investigated in this research for their pharmacotherapeutic effects were: Withania somnifera, Zingiber officinale, Moringa oleifera, Azadirachta indica and Aloe barbadensis. Results: The search yielded a total of 4803 papers published between the year 2000–2021 for further analysis. A total of 4726 articles (reports, reviews, and less relevant research papers) were excluded as they did not meet the inclusion criteria. A cumulative sum of 77 articles including research papers and reviews detailing in vivo and in vitro experiments of the specific plants of interest, with demonstrated activity met the inclusion criteria, and have been discussed in the present review. Conclusion: The pharmacological activities of the selected plant species have been demonstrated to inhibit cyclooxygenase 2, inhibit immunomodulation, suppress angiogenesis, inhibit proliferation, induce apoptosis, and reduction of oxidative stress with sufficient anti-colorectal cancer effects. These essential mechanisms make them befitting alternative options to synthetic chemotherapeutic options. In vivo studies are however encouraged in Moringa oleifera that has a significant gap identified through our search. In addition, more research is encouraged to document sufficient dose levels enough to elicit anti-colorectal cancer effects among the reviewed plants.

A series of novel 2-pyridyl, 4-morpholinyl substituted thiazolo[5,4-b]pyridine analogues have been designed and synthesized in this paper. These thiazolo[5,4-b]pyridines were efficiently prepared in seven steps from commercially available substances in moderate to good yields. All of these N-heterocyclic compounds were characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) analysis and tested for phosphoinositide 3-kinase (PI3K) enzymatic assay. The results indicated that these N-heterocyclic compounds showed potent PI3K inhibitory activity, and the IC50 of a representative compound (19a) could reach to 3.6 nm. The structure−activity relationships (SAR) study showed that sulfonamide functionality was important for PI3Kα inhibitory activity, and 2-chloro-4-florophenyl sulfonamide (19b), or 5-chlorothiophene-2-sulfonamide (19c) showed potent inhibitory activity with a nanomolar IC50 value. The pyridyl attached to thiazolo[5,4-b]pyridine was another key structural unit for PI3Kα inhibitory potency, and replacement by phenyl lead to a significant decrease in activity. Enzymatic Inhibition results showed that compound 19a inhibited PI3Kα, PI3Kγ, or PI3Kδ with a nanomolar IC50 value, but its inhibitory activity on PI3Kβ was approximately 10-fold reduced. Further docking analysis revealed that the N-heterocyclic core of compound 19a was directly involved in the binding to the kinase through the key hydrogen bonds interaction.

A new series of N-pyridyl-hydrazone derivatives was synthesized by using a simple and efficient method. The final compounds obtained were screened for their inhibitory potency against monoamine oxidase (MAO) A and B. The newly synthesized compounds 2a-2n specifically inhibited monoamine oxidases, displaying notably low IC50 values. Compounds 2i and 2j, with a CF3 and OH group on the 4-position of the phenyl ring, respectively, showed considerable MAO-A and MAO-B inhibitory activities. Compounds 2k, 2l and 2n, with N-methylpyrrole, furan and pyridine moieties instead of the phenyl ring, were the most powerful and specific inhibitors of MAO-A, with IC50 values of 6.12 µM, 10.64 µM and 9.52 µM, respectively. Moreover, these active compounds were found to be non-cytotoxic to NIH/3T3 cells. This study supports future studies aimed at designing MAO inhibitors to obtain more viable medications for neurodegenerative disorders, such as Parkinson's disease. [ABSTRACT FROM AUTHOR]

A new series of N-pyridyl-hydrazone derivatives was synthesized by using a simple and efficient method. The final compounds obtained were screened for their inhibitory potency against monoamine oxidase (MAO) A and B. The newly synthesized compounds 2a–2n specifically inhibited monoamine oxidases, displaying notably low IC50 values. Compounds 2i and 2j, with a CF3 and OH group on the 4-position of the phenyl ring, respectively, showed considerable MAO-A and MAO-B inhibitory activities. Compounds 2k, 2l and 2n, with N-methylpyrrole, furan and pyridine moieties instead of the phenyl ring, were the most powerful and specific inhibitors of MAO-A, with IC50 values of 6.12 μM, 10.64 μM and 9.52 μM, respectively. Moreover, these active compounds were found to be non-cytotoxic to NIH/3T3 cells. This study supports future studies aimed at designing MAO inhibitors to obtain more viable medications for neurodegenerative disorders, such as Parkinson’s disease.

Inhibitors of the sarco/endoplasmic reticulum calcium ATPase (SERCA) are valuable research tools and hold promise as a new generation of anti-prostate cancer agents. Based on previously determined potencies of phenolic SERCA inhibitors, we created quantitative structure-activity relationship (QSAR) models using three independent development strategies. The obtained QSAR models facilitated virtual screens of several commercial compound collections for novel inhibitors. Sixteen compounds were subsequently evaluated in SERCA activity inhibition assays and 11 showed detectable potencies in the micro- to millimolar range. The experimental results were then incorporated into a comprehensive master QSAR model, whose physical interpretation by partial least squares analysis revealed that properly positioned substituents at the central phenyl ring capable of forming hydrogen bonds and of undergoing hydrophobic interactions were prerequisites for effective SERCA inhibition. The established SAR was in good agreement with findings from previous structural studies, even though it was obtained independently using standard QSAR methodologies. [ABSTRACT FROM AUTHOR]

Abstract: Inhibitors of the transmembrane protein sarco/endoplasmic reticulum calcium ATPase (SERCA) are invaluable tools for the study of the enzyme''s physiological functions and they have been recognized as a promising new class of anticancer agents. For the discovery of novel enzyme inhibitors, small molecule docking for virtual screens of large compound libraries has become increasingly important. Since the performance of various docking routines varies considerably, depending on the target and the chemical nature of the ligand, we critically evaluated the performance of four frequently used programs — GOLD, AutoDock, Surflex-Dock, and FRED — for the docking of SERCA inhibitors based on the structures of thapsigargin, di-tert-butylhydroquinone, and cyclopiazonic acid. Evaluation criteria were docking accuracy using crystal structures as references, docking reproducibility, and correlation between docking scores and known bioactivities. The best overall results were obtained by GOLD and FRED. Docking runs with conformationally flexible binding sites produced no significant improvement of the results. [Copyright &y& Elsevier]

The inhibitory effects of diesel exhaust components and flavonoids on 20α-hydroxysteroid dehydrogenase (20α-HSD) activity were examined in cytosolic fractions from the liver, kidney and lung of male mice. 9,10-Phenanthrenequinone (9,10-PQ) and 1,2-naphthoquinone (1,2-NQ), which are contained in diesel exhaust particles (DEPs), potently inhibited 20α-HSD activity in liver cytosol. 9,10-PQ also inhibited the enzyme activity in lung cytosol. However, 20α-HSD activity in kidney cytosol was little inhibited by 9,10-PQ or 1,2-NQ. Flavonoids such as quercetin, fisetin and kaempferol exhibited high inhibitory potencies for 20α-HSD activity in liver cytosol, whereas these flavonoids were poor inhibitors for the enzyme activity in kidney cytosol. It is likely that several diesel exhaust components and flavonoids augment the signaling of progesterone in the liver cells, by potently inhibiting 20α-HSD activity in mouse liver cytosol. The possibility that there are distinct enzymes catalyzing 20α-HSD activity in the non-reproductive tissues of male mice is also discussed. [ABSTRACT FROM AUTHOR]

Abstract: Progesterone was stereoselectively reduced to a metabolite 20α-hydroxy-4-pregnen-3-one in the cytosolic fraction from the liver of male mice, indicating that the reduction of progesterone is catalyzed by 20α-hydroxysteroid dehydrogenase (20α-HSD). The cytosolic 20α-HSD activity was observed not only in the liver, but also in the kidney and lung. In liver cytosol, both NADPH and NADH were effective as cofactors for 20α-HSD activity, although NADPH was better than NADH for the enzyme activity. On the other hand, 20α-HSD activity in kidney cytosol required only NADPH as a cofactor. No significant sex-related difference of 20α-HSD activity was observed in liver and kidney cytosols. Flavonoids have been reported to inhibit the biosynthesis and metabolism of steroids. However, little is known about inhibitory effects of flavonoids on 20α-HSD activity. Thus, the effects of 16 flavonoids on 20α-HSD activity were examined, using liver cytosol of male mice. Among flavonoids tested, fisetin, apigenin, naringenin, luteolin, quercetin and kaempferol exhibited high inhibitory potencies for the 20α-HSD activity. We propose the possibility that these flavonoids augment progesterone signaling by inhibiting potently 20α-HSD activity in non-reproductive tissues. [Copyright &y& Elsevier]

Abstract: The first aim of this study is to characterize the reduction of progesterone in rat liver. Progesterone was mainly reduced to 20α-hydroxyprogesterone in the cytosolic fraction of rat liver. The amount of 20α-hydroxyprogesterone formed from progesterone in the cytosolic fraction was significantly larger in the males than in the females and this enzyme reaction proceeded not only in the presence of NADPH, but also in the presence of NADH. Furthermore, we attempted to evaluate the inhibitory effects of 15 flavonoids on the NADPH-dependent reduction of progesterone to 20α-hydroxyprogesterone in liver cytosol of male rats. The order of the inhibitory potencies was luteolin>apigenin>quercetin>myricetin=fisetin=kaempferol. Other flavonoids exhibited lower inhibitory potencies. Energy-minimized molecular models demonstrated that a planar benzopyrone ring (A and C rings) with a coplanar phenyl ring (B ring) is a structural characteristic determining the inhibitory effects of flavonoids other than isoflavones. [Copyright &y& Elsevier]

We investigated the inhibitory effects of nicardipine on airway smooth muscle constriction in the guinea pig via both in vitro and in vivo preparations. In the in vitro studies, we created dose-response curves of the excised tracheal strip. The increase in respiratory overflow produced by leukotriene (LT) D was measured in the in vivo preparation. In the organ bath, nicardipine (1-12 µg/ml) significantly inhibited constriction of the isolated tracheal spiral strip induced by 7 different agonists, acetylcholine (Ach), histamine (HA), serotonin (5-HT), prostaglandin F (PGF), slow-reacting substance of anaphylaxis (SRS-A), and LTC and LTD. Compared to nifedipine and verapamil (data in the literature), the inhibitory potency of nicardipine on the constriction of the isolated guinea pig tracheal strip is 100-1,000 times greater. In the in vivo studies, nicardipine (50 and 100 µg/kg) significantly attenuated the LTD-induced increase in respiratory overflow. These results suggest that nicardipine inhibits bronchoconstrictor-induced constriction of airway smooth muscle both in vitro and in vivo, and that it is a potent bronchodilator. The inhibitory characteristics of nicardipine may prove to be applicable clinically. [ABSTRACT FROM AUTHOR]

A series of novel 2-pyridyl, 4-morpholinyl substituted thiazolo[5,4-b]pyridine analogues have been designed and synthesized in this paper. These thiazolo[5,4-b]pyridines were efficiently prepared in seven steps from commercially available substances in moderate to good yields. All of these N-heterocyclic compounds were characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) analysis and tested for phosphoinositide 3-kinase (PI3K) enzymatic assay. The results indicated that these N-heterocyclic compounds showed potent PI3K inhibitory activity, and the IC50 of a representative compound (19a) could reach to 3.6 nm. The structure−activity relationships (SAR) study showed that sulfonamide functionality was important for PI3Kα inhibitory activity, and 2-chloro-4-florophenyl sulfonamide (19b), or 5-chlorothiophene-2-sulfonamide (19c) showed potent inhibitory activity with a nanomolar IC50 value. The pyridyl attached to thiazolo[5,4-b]pyridine was another key structural unit for PI3Kα inhibitory potency, and replacement by phenyl lead to a significant decrease in activity. Enzymatic Inhibition results showed that compound 19a inhibited PI3Kα, PI3Kγ, or PI3Kδ with a nanomolar IC50 value, but its inhibitory activity on PI3Kβ was approximately 10-fold reduced. Further docking analysis revealed that the N-heterocyclic core of compound 19a was directly involved in the binding to the kinase through the key hydrogen bonds interaction. [ABSTRACT FROM AUTHOR]

• Efficient synthesis of 1,3,4-thiadiazole-4-thiazolidinone hybrids modified at the 5th position of thiadiazole and/or thiazolidinone. • The in vitro and in vivo anti-inflammatory activities were determined. These activities affected significantly by the size of the substituent at the 5th position. • New compounds with potent dual COX-2/15-LOX inhibition, good in vivo activity and good gastric safety profile were obtained. Herin we report the design, synthesis, full characterization and biological investigation of new 15-LOX/COX dual inhibitors based on 1,3-thiazolidin-4-one (15-lipoxygenase pharmacophore) and 1,3,4-thiadiazole (COX pharmacophore) scaffolds. This series of molecular modifications is an extension of a previously reported series to further explore the structural activity relationship. Compounds 3a , 4e , 4n , 4q, 7 and 8 capable of inhibiting 15-LOX at (2.74, 4.2, 3.41, 10.21, 3.71 and 3.36 µM, respectively) and COX-2 at (0.32, 0.28, 0.28, 0.1, 0.28 and 0.27 µM, respectively). The results revealed that binding to 15-LOX and COX is sensitive to the bulkiness of the substituents at the 5 positions. 15-LOX bind better with small substituents, while COXs bind better with bulky substituents. Compounds 3a , 4r and 4q showed comparable in vivo anti-inflammatory activity to the reference drug (celecoxib). The ulcer liability test showed no sign of ulceration which ensures the safe gastric profile. Docking study was performed to explore the possible mode of interaction of the new compounds with the active site of human 15-LOX and COX-2. This study discloses some structural features for binding to 15-LOX and COX, thus pave the way to design anti-inflammatory agents with balanced dual inhibition of these enzymes. [ABSTRACT FROM AUTHOR]

Background: Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anticancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and belinostat (PXD-101)., Aims: This study aims at developing novel HDAC inhibitors bearing N-hydroxybenzamides and Nhydroxypropenamides scaffolds with potential cytotoxicity against different cancer cell lines., Methods: Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships., Results: It was found that the N-hydroxypropenamides (6a-e) displayed very good HDAC inhibitory potency and cytotoxicity. Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in terms of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in the sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities., Conclusions: The two series of N-hydroxybenzamides and N-hydroxypropenamides designed and synthesized were potential HDAC inhibitors and antitumor agents. Further development of these compounds should be warranted., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)