Showing papers in "Archiv Der Pharmazie in 2023"

Design, synthesis, molecular docking, and biological evaluation of coumarin‐thymidine analogs as potent anti‐TB agents

Abstract: With the intent to discover new antituberculosis (TB) compounds, coumarin‐thymidine analogs were synthesized using second‐order nucleophilic substitution reactions of bromomethyl coumarin with thymidine. The newly synthesized coumarin‐thymidine conjugates (1a–l) were characterized using IR, NMR, GC‐MS, and CHN elemental analysis. The novel conjugates were found to exhibit potent anti‐TB activity against the Mycobacterium tuberculosis H37Rv strain, with minimum inhibitory concentrations (MIC) of the active compounds ranging between 0.012 and 0.482 µM. Compound 1k was established as the most active candidate with a MIC of 0.012 µM. The toxicity study on HEK cells confirmed the nontoxic nature of compounds 1e, 1h, 1i, 1j, and 1k. Also, the most active compounds (1k, 1j, and 1e) were stable in the pH range from 2.5 to 10, indicating compatibility with the biophysical environment. Based on the pKa studies, compounds 1k, 1j, and 1e are capable of crossing lipid‐membrane barriers and acting on target cells. Molecular docking studies on the M. tuberculosis β‐oxidation trifunctional enzyme (PDB ID: 7O4V) were conducted to investigate the mechanisms of anti‐TB activity. All compounds showed excellent hydrogen binding interactions and exceptional docking scores against M. tuberculosis, which was in accordance with the results. Compounds 1a–l possessed excellent affinity to proteins, with binding energies ranging from −7.4 to −8.7 kcal/mol.

Zinc(II) complexation strategy for ultra‐sensitive fluorimetric estimation of molnupiravir: Applications and greenness evaluation

Abstract: The endemicity of the pandemic coronavirus disease 2019 (COVID‐19) infection proved to be transitional only. Spikes are forming again in 2023, and high expectations are returning for reinfections and viral mutations. Molnupiravir (MOL) has been approved as an oral antiviral drug for the treatment of the COVID‐19 causative virion. Therefore, the development of an ultrasensitive, instantaneous, and cost‐effective method for the quantification of MOL in real plasma samples and formulated dosage form are mandatory. The proposed approach is based on the synthesis of a MOL metal‐chelation product. MOL as a ligand was chelated with 1.0 mM zinc(II) in an acetate buffer (pH 5.3). After illumination at 340 nm, the intensity of the MOL fluorescence measured at 386 nm was increased by about 10‐fold. The linearity range was found to be from 60.0 to 800.0 ng mL−1 with limit of quantitation (LOQ) of 28.6 ng mL−1. Two methods were utilized for measuring the greenness of the proposed method (Green Analytical Procedure Index [GAPI] and analytical greenness metric [AGREE] methods), with results equal to 0.8. The binding stoichiometry of MOL with the zinc(II) ion was found to be 2:1. All the experimental parameters were optimized and validated using International Conference on Harmonization (ICH) and United States Food and Drug Administration (US‐FDA) recommendations. Furthermore, the fluorescent probes were successfully utilized in real human plasma with high percentages of recovery (95.6%–97.1%) without any matrix interferences. The mechanism of fluorescent complex formation was confirmed using 1H NMR in the presence and absence of Zn(II). The method was further utilized for testing content uniformity of MOL in its marketed capsule dosage forms.

Influence of the pKa value on the antioxidant activity of licorice flavonoids under solvent‐mediated effects

Abstract: Licorice flavonoids (LCFs) have been widely used in food care and medical treatment due to their significant antioxidant activities. However, the molecular mechanism of their antioxidant activity remains unclear. Therefore, network pharmacology, ADMET, density functional theory (DFT), molecular docking, and molecular dynamics (MD) simulation were employed to explore the molecular mechanism of the antioxidant effects of LCF. The network pharmacology and ADMET studies showed that the active molecules of kumatakenin (pKa = 6.18), licoflavonol (pKa = 6.86), and topazolin (pKa = 6.21) in LCF are key antioxidant components and have good biosafety. Molecular docking and MD simulation studies demonstrated that active molecules interacted with amino acid residues in target proteins to form stable protein–ligand complexes and exert their antioxidant effects. DFT studies showed that the antioxidant activity of LCF could be significantly modulated under the solvent‐mediated effect. In addition, based on the derivation of the Henderson–Hasselbalch and van't Hoff formulas, the functional relationships between the reaction‐free energy (ΔG) of LCF and the pH and pKa values were established. The results showed that active molecules with larger pKa values will be more conducive to the improvement of their antioxidant activity under solvent‐mediated effects. In conclusion, this study found that increasing the pKa value of LCF would be an effective strategy to improve their antioxidant activity under the effect of solvent mediation. The pKa value of an LCF will be a direct standard to evaluate its solvent‐mediated antioxidant activity. This study will provide theoretical guidance for the development of natural antioxidants.

Dihydropyrimidinones as potent anticancer agents: Insight into the structure–activity relationship

Abstract: Cancer is a serious disease that has been around for a long time but currently has no sustainable solution. Several medications currently available offer an opportunity for the manifestation of cancer treatment; however, the “search for better” has led to the development and study of a variety of new scaffolds. Dihydropyrimidinones (DHPMs) are a privileged scaffold, prominent for their versatile range of biological activities. In recent years, the anticancer potential of these unsaturated pyrimidine ring systems has been traversed, along with their synthesis methods and the interlinked mechanisms leading to the anticancer activity. This review summarizes the structure–activity relationship of DHPMs as potential anticancer agents. This study is a short review of their synthesis, mechanism of action, and structure–activity relationships (SARs) that are answerable for the anticancer activity of DHPMs and have been thoroughly researched and assessed.

Design, synthesis, and docking of novel thiazolidine‐2,4‐dione multitarget scaffold as new approach for cancer treatment

Abstract: Novel thiazolidine‐2,4‐diones have been developed and estimated as conjoint inhibitors of EGFRT790M and VEGFR‐2 against HCT‐116, MCF‐7, A549, and HepG2 cells. Compounds 6a, 6b, and 6c were known to be the dominant advantageous congeners against HCT116 (IC50 = 15.22, 8.65, and 8.80 µM), A549 (IC50 = 7.10, 6.55, and 8.11 µM), MCF‐7 (IC50 = 14.56, 6.65, and 7.09 µM) and HepG2 (IC50 = 11.90, 5.35, and 5.60 µM) mass cell lines, correspondingly. Although compounds 6a, 6b, and 6c disclosed poorer effects than sorafenib (IC50 = 4.00, 4.04, 5.58, and 5.05 µM) against the tested cell sets, congeners 6b and 6c demonstrated higher actions than erlotinib (IC50 = 7.73, 5.49, 8.20, and 13.91 µM) against HCT116, MCF‐7 and HepG2 cells, yet lesser performance on A549 cells. The hugely effective derivatives 4e–i and 6a–c were inspected versus VERO normal cell strains. Compounds 6b, 6c, 6a, and 4i were found to be the most effective derivatives, which suppressed VEGFR‐2 by IC50 = 0.85, 0.90, 1.50, and 1.80 µM, respectively. Moreover, compounds 6b, 6a, 6c, and 6i could interfere with the EGFRT790M performing strongest effects with IC50 = 0.30, 0.35, 0.50, and 1.00 µM, respectively. What is more, 6a, 6b, and 6c represented satisfactory in silico computed ADMET profile.

Triazolo‐linked benzimidazoles as tubulin polymerization inhibitors and DNA intercalators: Design, synthesis, cytotoxicity, and docking studies

Abstract: A simple “click” protocol was employed in the quest of synthesizing 1,2,3‐triazole‐linked benzimidazoles as promising anticancer agents on various human cancer cell lines such as A549, HCT116, SK‐Mel‐28, HT‐29, and MCF‐7. Compound 12j demonstrated significant cytotoxic potential towards SK‐Mel‐28 cancer cells (IC50: 4.17 ± 0.09 µM) and displayed no cytotoxicity (IC50: > 100 µM) against normal human BEAS‐2B cells inferring its safety towards normal healthy cells. Further to comprehend the underlying apoptosis mechanisms, AO/EB, dichlorodihydrofluorescein diacetate (DCFDA), and 4',6‐diamidino‐2‐phenylindole (DAPI) staining were performed, which revealed the nuclear and morphological alterations. Compound 12j displayed impairment in cellular migration and inhibited colony formation. The annexin V binding assay and JC‐1 were implemented to evaluate the scope of apoptosis and the loss of the mitochondrial transmembrane potential in SK‐Mel‐28 cells. Cell‐cycle analysis revealed that compound 12j arrested the cells at the G2/M phase in a dose‐dependent manner. Target‐based assays established the inhibition of tubulin polymerization by 12j at an IC50 value of 5.65 ± 0.05 μM and its effective binding with circulating tumor DNA as a DNA intercalator. The detailed binding interactions of 12j with tubulin and DNA were examined by docking studies on PDB ID: 3E22 and DNA hexamer (PDB ID: 1NAB), respectively.

The synergy between nucleotide biosynthesis inhibitors and antiviral nucleosides: New opportunities against viral infections?

Abstract: 5'-Phosphorylated nucleoside derivatives are molecules that can be found in all living organisms and viruses. Over the last century, the development of structural analogs that could disrupt the transcription and translation of genetic information culminated in the development of clinically relevant anticancer and antiviral drugs. However, clinically effective broad-spectrum antiviral compounds or treatments are lacking. This viewpoint proposes that molecules that inhibit nucleotide biosynthesis may sensitize virus-infected cells toward direct-acting antiviral nucleosides. Such potentially synergistic combinations might allow the repurposing of drugs, leading to the development of new combination therapies.

Synthesis of selenophene‐based chalcone analogs and assessment of their biological activity as anticancer agents

Abstract: Selenium is an essential micronutrient that is beneficial to human health. Selenium‐containing drugs have been developed as antioxidants, anti‐inflammatory, and anticancer agents. However, the synthesis of selenium‐containing chalcones has not been fully explored. Therefore, we report the synthesis of novel selenophene‐based chalcone analogs and reveal their biological activities as anticancer agents. Among the seven synthesized molecules, compounds 6, 8, and 10 exhibited anticancer activity with IC50 values of 19.98 ± 3.38, 38.23 ± 3.30, and 46.95 ± 5.68 μM, respectively, against human colorectal adenocarcinoma (HT‐29) cells. Clonogenic assays and Western blot analysis tests further confirmed that compound 6 effectively induced apoptosis in HT‐29 cells through mitochondrial‐ and caspase‐3‐dependent pathways.

Novel promising benzoxazole/benzothiazole-derived immunomodulatory agents: Design, synthesis, anticancer evaluation, and in silico ADMET analysis.

Abstract: Eleven novel benzoxazole/benzothiazole-based thalidomide analogs were designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against HepG-2, HCT-116, PC3, and MCF-7 cells. Generally, the open analogs with semicarbazide and thiosemicarbazide moieties (10, 13a-c, 14, and 17a,b) exhibited higher cytotoxic activities than derivatives with closed glutarimide moiety (8a-d). In particular, compound 13a (IC50 = 6.14, 5.79, 10.26, and 4.71 µM against HepG-2, HCT-116, PC3, and MCF-7, respectively) and 14 (IC50 = 7.93, 8.23, 12.37, and 5.43 µM, respectively) exhibited the highest anticancer activities against the four tested cell lines. The most active compounds 13a and 14 were further evaluated for their in vitro immunomodulatory activities on tumor necrosis factor-alpha (TNF-α), caspase-8 (CASP8), vascular endothelial growth factor (VEGF), and nuclear factor kappa-B p65 (NF-κB p65) in HCT-116 cells. Compounds 13a and 14 showed a remarkable and significant reduction in TNF-α. Furthermore, they showed significant elevation in CASP8 levels. Also, they significantly inhibited VEGF. In addition, compound 13a showed significant decreases in the level of NF-κB p65 while compound 14 demonstrated an insignificant decrease with respect to thalidomide. Moreover, our derivatives exhibited good in silico absorption, distribution, metabolism, elimination, toxicity (ADMET) profiles.

Synthesis and biological evaluation of benzamide‐chalcone hybrids as potential c‐Met kinase and COX‐2 inhibitors

Abstract: c‐Met kinase and cyclooxygenase 2 (COX‐2) enzymes are two significant targets in tumor progression. Chalcone and benzamide moieties were combined using molecular hybridization to assess their potential as c‐Met kinase and COX‐2 inhibitors. 4‐Methylbenzamide and 4‐chlorobenzamide chalcone analogs were synthesized, characterized, and evaluated for antiproliferative activity on Michigan Cancer Foundation‐7 (MCF‐7), HT‐29, MDA‐MB‐231, COLO‐205, and A549 cell lines by sulforhodamine‐B stain (SRB) assay. Following the SRB assay, compounds were evaluated for their c‐Met kinase and COX‐2 inhibitory potential. All compounds inhibited COX‐2 with half‐maximal inhibitory concentration (IC50) <10 µM. Compounds 7h, 7i, 7j, 8f, and 8j inhibited c‐Met with IC50 <10 µM. Compound 7h was evaluated for its long‐term antiproliferative and anti‐migratory effects by colony formation and wound healing assay. It exerted these effects in a concentration‐dependent manner. Compounds 7j and 8j were further evaluated for in vitro antiangiogenic effects. Compound 7j exhibited moderate antiangiogenic effect while compound 8j exhibited strong effect. Compounds 7h, 7i, 7j, 8f, and 8j were evaluated for the serum protein binding, using the in vitro bovine serum albumin binding assay. The results indicated that the tested compounds bind to bovine serum albumin (BSA) and can be further explored by other studies.

Tetrahydroquinazoline N‐oxide derivatives inhibit reproduction of tick‐borne and mosquito‐borne flaviviruses

Abstract: Tick‐borne encephalitis virus (TBEV), yellow fever virus (YFV), and West Nile virus (WNV) are flaviviruses causing emerging arthropod‐borne infections of a great public health concern. Clinically approved drugs are not available to complement or replace the existing vaccines, which do not provide sufficient coverage. Thus, the discovery and characterization of new antiflaviviral chemotypes would advance studies in this field. In this study, a series of tetrahydroquinazoline N‐oxides was synthesized, and the antiviral activity of the compounds was assessed against TBEV, YFV, and WNV using the plaque reduction assay along with the cytotoxicity to the corresponding cell lines (porcine embryo kidney and Vero). Most of the studied compounds were active against TBEV (EC50 2 to 33 μM) and WNV (EC50 0.15 to 34 μM) and a few also demonstrated inhibitory activity against YFV (EC50 0.18 to 41 μM). To investigate the potential mechanism of action of the synthesized compounds, time‐of‐addition (TOA) experiments and virus yield reduction assays were performed for TBEV. The TOA studies suggested that the antiviral activity of the compounds should affect the early stages of the viral replication cycle after cell entry. Compounds with tetrahydroquinazoline N‐oxide scaffold show a broad spectrum of activity against flaviviruses and represent a promising chemotype for antiviral drug discovery.

New benzimidazole‐oxadiazole derivatives: Synthesis, α‐glucosidase, α‐amylase activity, and molecular modeling studies as potential antidiabetic agents

Abstract: Benzimidazole‐1,3,4‐oxadiazole derivatives (5a–z) were synthesized and characterized with different spectroscopic techniques such as 1H NMR, 13C NMR, and HRMS. The synthesized analogs were examined against α‐glucosidase and α‐amylase enzymes to determine their antidiabetic potential. Compounds 5g and 5q showed the most activity with 35.04 ± 1.28 and 47.60 ± 2.16 µg/mL when compared with the reference drug acarbose (IC50 = 54.63 ± 1.95 µg/mL). Compounds 5g, 5o, 5s, and 5x were screened against the α‐amylase enzyme and were found to show excellent potential, with IC50 values ranging from 22.39 ± 1.40 to 32.07 ± 1.55 µg/mL, when compared with the standard acarbose (IC50 = 46.21 ± 1.49 µg/mL). The antioxidant activities of the effective compounds (5o, 5g, 5s, 5x, and 5q) were evaluated by TAS methods. A molecular docking research study was conducted to identify the active site and explain the functions of the active chemicals. To investigate the most likely binding mode of the substances 5g, 5o, 5q, 5s, and 5x, a molecular dynamics simulation was also carried out.

Coumaryl‐sulfonamide moiety: Unraveling their synthetic strategy and specificity toward hCA IX/XII, facilitating anticancer drug development

Abstract: Currently, cancer is the most grieving threat to society. The cancer‐related death rate has had an ascending trend, despite the implementation of numerous treatment strategies or the discovery of an array of potent molecules against several pathways of cancer growth. The need of the hour is to prevent the multidrug resistance toll, and the current efforts have been bestowed upon a versatile small molecule scaffold, coumarin (benz[α]pyrone), a natural compound possessing interesting affinity toward the cancer target human carbonic anhydrase (hCA), focusing on hCA I, II, IX, and XII. Along with coumarin, the age‐old known antibacterial drug sulfonamide, when conjugated at positions 3, 7, and 8 of coumarin either with a linker group or as a single entity, has been reported to enhance the affinity of coumarin toward the overexpressed enzymes in tumor cell lines. The sulfonamides have been listed as obsolete drugs due to the severe side effects caused by them; however, their affinity toward the hCA‐zinc–binding core has attracted the attention of researchers. Hence, in the process of drug development, coumarin and sulfonamides have remained the choice of last resort. To unveil the synthetic strategy of coumarin‐sulfonamide conjugation, their rationale for inhibiting cancer cells/enzymes, and their affinity toward various types of carcinoma have been the sole goal of the researchers. This review specifically focuses on the mechanism of action and the structure–activity relationship through synthetic strategies and the binding affinity of coumaryl‐sulfonamide conjugates with the anticancer targets possessing the highest enzyme affinity, since 2008.

Synthesis and evaluation of multitarget new 2-aminothiazole derivatives as potential anti-Alzheimer's agents.

Abstract: In this study, two diverse series of 2-aminothiazole-based multitarget compounds, one propenamide and the other propanamide derivatives, were designed and synthesized. Subsequently, their anticholinesterease and antioxidant (ORAC) activities were tested. Among them, compound 3e was the most potent acetylcholinesterase (AChE) inhibitor (AChE IC50 = 0.5 μM, butyrylcholinesterase [BChE] IC50 = 14.7 μM) and compound 9e was the most potent BChE inhibitor (AChE IC50 = 3.13 μM, BChE IC50 = 0.9 μM). Kinetic experiments showed that both compounds were mixed-type inhibitors. According to the anticholinesterease activity results, five compounds (3e, 4e, 5e, 9d, and 9e) were selected for further activity studies, all of which are dual cholinesterase inhibitors. Then, selected compounds were investigated in terms of their metal chelation activity. Moreover, their neuroprotective effects against H2 O2 -induced damage in the PC12 cell line were evaluated at 10 μM and the results showed that the neuroprotective effect of 3e was 53% compared with the reference ferulic acid (77%). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) results of selected compounds revealed that the compounds were noncytotoxic. Additionally, 3e was more effective in reducing lipopolysaccharides-induced interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and nitric oxide (NO) production in the human monocyte derived from patient with acute monocytic leukemia cell line compared with other selected compounds. Finally, a molecular docking study was also performed.

Greenness-by-design approach for developing novel UV spectrophotometric methodologies resolving a quaternary overlapping mixture.

Abstract: Greenness-by-design (GbD) is an approach that integrates green chemistry principles into the method development stage of analytical processes, aiming to reduce their environmental impact. In this work, we applied GbD to a novel univariate double divisor corrected amplitude (DDCA) method that can resolve a quaternary pharmaceutical mixture in a fixed-dose polypill product. We also used a genetic algorithm as a chemometric modeling technique to select the informative variables for the analysis of the overlapping mixture. This resulted in more accurate and efficient predictive models. We used a computational approach to study the effect of solvents on the spectral resolution of the mixture and to minimize the spectral interferences caused by the solvent, thus achieving spectral resolution with minimal analytical effort and ecological footprint. The validated methods showed wide linear concentration ranges for the four components (1-30 µg/mL for losartan, 2.5-30 µg/mL for atorvastatin and aspirin, and 2.5-35 µg/mL for atenolol) and achieved high scores on the hexagon and spider charts, demonstrating their eco-friendliness.

Synthesis of 1,2,3-triazole-1,3,4-thiadiazole hybrids as novel α-glucosidase inhibitors by in situ azidation/click assembly.

Abstract: α-Glucosidase inhibition is widely used in the oral management of diabetes mellitus (DM), a disease characterized by high blood sugar levels (hyperglycemia) and abnormal carbohydrate metabolism. In this respect, a series of 1,2,3-triazole-1,3,4-thiadiazole hybrids 7a-j were synthesized, inspired by a copper-catalyzed one-pot azidation/click assembly approach. All the synthesized hybrids were screened for inhibition of the α-glucosidase enzyme, displaying IC50 values ranging from 63.35 ± 0.72 to 613.57 ± 1.98 μM, as compared to acarbose (reference) with IC50 of 844.81 ± 0.53 μM. The hybrids 7h and 7e with 3-nitro and 4-methoxy substituents at the phenyl ring of the thiadiazole moiety were the best active hybrids of this series with IC50 values of 63.35 ± 0.72 μM, and 67.61 ± 0.64 μM, respectively. Enzyme kinetics analysis of these compounds revealed a mixed mode of inhibition. Moreover, molecular docking studies were also performed to gain insights into the structure-activity-relationships of the potent compounds and their corresponding analogs.

Synthesis and structure–activity relationships of USP48 deubiquitinylase inhibitors

Abstract: Ubiquitin‐specific proteases represent a family of enzymes that catalyze the cleavage of ubiquitin from specific substrate proteins to regulate their activity. USP48 is a rarely studied USP, which has recently been linked to inflammatory signaling via regulation of the transcription factor nuclear factor kappa B. Nonetheless, a crystal structure of USP48 has not yet been resolved and potent inhibitors are not known. We screened a set of 14 commercially available USP inhibitors for their activity against USP48 and identified the USP2 inhibitor “ML364” as a candidate for further optimization. Using a ligand‐based approach, we derived and synthesized a series of ML364 analogs. The IC50 concentrations of the new compounds to inhibit USP48 were determined in a deubiquitinylase activity assay by measuring the fluorescence intensity using tetra‐ubiquitin rhodamine110 as substrate. A compound containing a carboxylic acid functionalization (17e) inhibited USP48 activity toward tetra‐ubiquitin rhodamine110 with an IC50 of 12.6 µM. Further structure‐based refinements are required to improve the inhibition activity and specificity.

In silico characterization of ligand-receptor interactions for U-47700, N,N-didesmethyl-U-47700, U-50488 at mu- and kappa-opioid receptors.

Abstract: The increasing misuse of novel synthetic opioids (NSOs) represents a serious public health concern. In this regard, U-47700 (trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide) and related "U-compounds" emerged on recreational drug markets as synthetic substitutes for illicit heroin and constituents of counterfeit pain medications. While the pharmacology of U-compounds has been investigated using in vitro and in vivo methods, there is still a lack of understanding about the details of ligand-receptor interactions at the molecular level. To this end, we have developed a molecular modeling protocol based on docking and molecular dynamics simulations to assess the nature of ligand-receptor interactions for U-47700, N,N-didesmethyl U-47700, and U-50488 at the mu-opioid receptor (MOR) and kappa-opioid receptor (KOR). The evaluation of ligand-receptor and ligand-receptor-membrane interaction energies enabled the identification of subtle conformational shifts in the receptors induced by ligand binding. Interestingly, the removal of two key methyl groups from U-47700, to form N,N-didesmethyl U-47700, caused a loss of hydrogen bond contact with tryptophan (Trp)229, which may underlie the lower interaction energy and reduced MOR affinity for the compound. Taken together, our results are consistent with the reported biological findings for U-compounds and provide a molecular basis for the MOR selectivity of U-47700 and KOR selectivity of U-50488.

Optimized synthesis and pharmacological evaluation of HCN channel inhibitor EC18

Abstract: HCN4 channels are considered to be a promising target for cardiac pathologies, epilepsy, and multiple sclerosis. However, there are no subtype‐selective HCN channel blockers available, and only a few compounds are reported to display subtype preferences, one of which is EC18 (cis‐1). Herein, we report the optimized synthetic route for the preparation of EC18 and its evaluation in three different pharmacological models, allowing us to assess its activity on cardiac function, thalamocortical neurons, and immune cells.

Curcumin-based bioactive heterocycles derived via multicomponent reactions.

Abstract: Curcumin is an important phytochemical, found in the Asian countries, especially in the Indian subcontinent. The use of this "privileged natural product" in the diversity-oriented synthesis of curcumin-based heterocycles via multicomponent reactions (MCRs) is the subject of interest for many medicinal chemists across the globe. This review particularly focuses on the reactions involving curcuminoids as one of the reactants in the MCRs of curcuminoid to synthesize curcumin-based heterocycles. Also, the various pharmacological activities of curcumin-based heterocycles generated via the MCR approach are discussed. The research work published in the last 10 years is in the focus of this review article.

Development of a multigram synthesis of the bradykinin receptor 2 agonist FR‐190997 and analogs thereof

Abstract: Using Fujisawa's B2R agonist FR‐190997, we recently demonstrated for the first time that agonism at the bradykinin receptor type 2 (B2R) produces substantial antiproliferative effects. FR‐190997 elicited an EC50 of 80 nM in the triple‐negative breast cancer cell line MDA‐MB‐231, a much superior performance to that exhibited by most approved breast cancer drugs. Consequently, we initiated a program aiming primarily at synthesizing adequate quantities of FR‐190997 to support further in vitro and in vivo studies toward its repurposing for various cancers and, in parallel, enable the generation of novel FR‐190997 analogs for an SAR study. Prerequisite for this endeavor was to address the synthetic challenges associated with the FR‐190997 scaffold, which the Fujisawa chemists had constructed in 20 steps, 13 of which required chromatographic purification. We succeeded in developing a 17‐step synthesis amenable to late‐stage diversification that eliminated all chromatography and enabled access to multigram quantities of FR‐190997 and novel derivatives thereof, supporting further anticancer research based on B2R agonists.

Editorial Board: Arch Pharm (5/2023)

Abstract: Archiv der PharmazieVolume 356, Issue 5 2370010 EDITORIAL BOARDFree Access Editorial Board: Arch Pharm (5/2023) First published: 04 May 2023 https://doi.org/10.1002/ardp.202370010AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume356, Issue5May 20232370010 RelatedInformation

Targeting the binding pocket of the fluorophore 8-anilinonaphthalene-1-sulfonic acid in the bacterial enzyme MurA.

Abstract: 8-Anilinonaphthalene-1-sulfonic acid (ANS) has been extensively used as a fluorescent probe to detect conformational changes of proteins. It has been cocrystallized with several of the proteins it is used to monitor, including the bacterial cell wall synthesis enzyme MurA. MurA catalyzes the first committed step of peptidoglycan biosynthesis, converting UDP-N-acetylglucosamine (UDP-GlcNAc) into enolpyruvyl UDP-GlcNAc. It has been reported before that ANS binds to MurA from Enterobacter cloacae without inhibiting the enzyme's activity up to a concentration of 1 mM ANS. In this study, we present evidence that ANS inhibits the activity of several isoforms of MurA with IC50 values of 18, 22, and 31 µM against wild-type Escherichia coli, C115D E. coli, and E. cloacae MurA, respectively. This prompted us to test a larger series of structural analogs of ANS for the inhibition of these MurA enzymes, which led to the discovery of compound 26. This ANS analog showed enhanced inhibition of MurA (WT and C115D MurA from E. coli, and E. cloacae MurA) with IC50 values of 2.7, 10, and 14 µM, respectively. Based on our results, the ANS binding pocket was identified as a novel target site for the development of potential antibiotics.

Development of heterodimeric estrogen receptor alpha antagonists to target simultaneously the ligand and coactivator binding site

Abstract: One‐third of breast cancer patients will develop recurrent cancer within 15 years of endocrine treatment. Notably, tumor growth in a hormone‐refractory state still relies on the interaction between estrogen receptor alpha (ERα) and upregulated coactivators. Herein, we suggest that simultaneous targeting of the primary ligand binding site (LBS) and the coactivator binding site (CABS) at ERα represents a promising alternative therapeutic strategy to overcome mutation‐driven resistance in breast cancer. We synthesized two series of compounds that connect the LBS‐binder (E)−3‐{4‐[8‐fluoro‐4‐(4‐hydroxyphenyl)‐2,3‐dihydrobenzo[b]oxepin‐5‐yl]phenyl}acrylic acid 8 with the coactivator binding site inhibitors (CBIs) 4,6‐bis(isobutyl(methyl)amino)pyrimidine or 3‐(5‐methoxy‐1H‐benzo[d]imidazol‐2‐yl)propanoic acid via covalent linkage. The most active benzoxepine‐pyrimidine conjugate 31 showed strong inhibition of estradiol‐induced transactivation (IC50 = 18.2 nM (ERα) and 61.7 nM (ERβ)) in a luciferase reporter gene assay as well as high antiproliferative effects in MCF‐7 (IC50 = 65.9 nM) and tamoxifen‐resistant MCF‐7/TamR (IC50 = 88.9 nM) breast cancer cells. All heterodimers exhibited two‐ to sevenfold higher antagonism at ERα (compared with ERβ) and were superior to the acrylic acid precursor 8 in terms of ER antagonism and antiproliferative activity. It was demonstrated on the example of 31 that the compounds did not influence the ERα content in MCF‐7 cells and therefore act as pure antiestrogens without downregulating potency. Possible interactions of the CBI at the receptor surface, which enhanced the biological activities, were evaluated using molecular docking studies.

Cover Picture: Arch Pharm (1/2023)

Abstract: Archiv der PharmazieVolume 356, Issue 1 2370001 COVER PICTUREFree Access Cover Picture: Arch Pharm (1/2023) First published: 02 January 2023 https://doi.org/10.1002/ardp.202370001AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume356, Issue1January 20232370001 RelatedInformation

A new series of hydrazones as small‐molecule aldose reductase inhibitors

Abstract: In the search for small‐molecule aldose reductase (AR) inhibitors, new tetrazole‐hydrazone hybrids (1–15) were designed. An efficient procedure was employed for the synthesis of compounds 1–15. All hydrazones were subjected to an in vitro assay to assess their AR inhibitory profiles. Compounds 1–15 caused AR inhibition with Ki values ranging between 0.177 and 6.322 µM and IC50 values ranging between 0.210 and 0.676 µM. 2‐[(1‐(4‐Hydroxyphenyl)‐1H‐tetrazol‐5‐yl)thio]‐N’‐(4‐fluorobenzylidene)acetohydrazide (4) was the most potent inhibitor of AR in this series. Compound 4 markedly inhibited AR (IC50 = 0.297 µM) in a competitive manner (Ki = 0.177 µM) compared to epalrestat (Ki = 0.857 µM, IC50 = 0.267 µM). Based on the in vitro data obtained by applying the MTT test, compound 4 showed no cytotoxic activity toward normal (NIH/3T3) cells at the tested concentrations, indicating its safety as an AR inhibitor. Compound 4 exhibited proper interactions with crucial amino acid residues within the active site of AR. In silico QikProp data of all hydrazones (1–15) were also determined to assess their pharmacokinetic profiles. Taken together, compound 4 stands out as a promising inhibitor of AR for further in vivo studies.

Editorial Board: Arch Pharm (2/2023)

Abstract: Archiv der PharmazieVolume 356, Issue 2 2370004 EDITORIAL BOARDFree Access Editorial Board: Arch Pharm (2/2023) First published: 01 February 2023 https://doi.org/10.1002/ardp.202370004AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume356, Issue2February 20232370004 RelatedInformation

Anticancer agents incorporating the N‐acylhydrazone scaffold: Progress from 2017 to present

Abstract: The N‐acylhydrazone motif has been shown to be particularly adaptable and promising in the area of medicinal chemistry and drug development, due to its significant biological and pharmacological characteristics. Moreover, N‐acylhydrazones are appealing synthetic and biological tools because of their simple and straightforward synthesis. This scaffold has emerged as a fundamental building block for the synthesis of bioactive compounds. Particularly, the N‐acylhydrazone scaffold served as a base for the synthesis of a number of potent anticancer agents acting via different mechanisms. An updated summary of the anticancer activity of N‐acylhydrazone derivatives described in the literature (from 2017 to 2022) is provided in the current review. It discusses the structure–activity relationship (SAR) of N‐acylhydrazone derivatives exhibiting anticancer potential, which could be helpful in designing and developing new derivatives as effective antiproliferative candidates in the future.

Synthesis and antimicrobial activity evaluation of pyrazole derivatives containing the imidazo[2,1-b][1,3,4]thiadiazole moiety.

Abstract: Four series of novel pyrazole derivatives (compounds 17a-m, 18a-m, 19a-g, and 20a-g) were synthesized, and their antibacterial and antifungal activities were evaluated. Most of the target compounds (17a-m, 18k-m, and 19b-g) showed strong antifungal activity and high selectivity relative to both Gram-positive and Gram-negative bacteria. Among them, compounds 17l (minimum inhibitory concentration [MIC] = 0.25 µg/mL) and 17m (MIC = 0.25 µg/mL) showed the strongest antifungal activity, being 2- and 4-fold more active than the positive controls gatifloxacin and fluconazole, respectively. In particular, compound 17l showed little cytotoxicity against human LO2 cells and did not exhibit hemolysis at ultrahigh concentrations, as did the positive control compounds gatifloxacin and fluconazole. These results indicate that these compounds are valuable for further development as antifungal agents.

The medicinal panorama of benzimidazoles and their scaffolds as anticancer and antithrombotic agents: A review.

Abstract: Nitrogen-containing heterocyclic scaffolds have become a prospective pharmacophore with therapeutic importance due to their biological similarities with natural and synthetic drugs. Among all nitrogen heterocyclic compounds, benzimidazoles and their derivatives are privileged molecules structurally akin to naturally available nucleotides, enabling them to intercommunicate with numerous biopolymers in biological systems. This reason enlightens modern researchers worldwide to assess their potential significance in the context of synthetic and biological chemistry. Therefore, it is crucial to merge the latest data with the prior documentation to apprehend the ongoing situation of the benzimidazole moiety in various therapeutic zones of research. The current work displays that the benzimidazole center is a versatile nucleus that offers the necessary data of synthetic alterations for pre-existing compounds to provide new scaffolds to resist numerous therapeutic sectors, including those associated with anticancer and antithrombosis. Due to the potential significance of benzimidazoles, this review aims to emphasize the latest innovations in synthesizing several other notable benzimidazole substrates and their significant pharmacological prospects for the future, including anticancer and antithrombosis.