Showing papers in "Archiv Der Pharmazie in 2022"

Design, synthesis, and biological activity of novel dithiocarbamate‐methylsulfonyl hybrids as carbonic anhydrase inhibitors

Abstract: Carbonic anhydrase (CA) enzymes are involved in many physiological events. These enzymes, which contain Zn2+ in their structure, can be easily inhibited by dithiocarbamate compounds. In addition, CA enzyme inhibitory activities are known in groups such as sulfonamide and methylsulfonyl. For this purpose, in this study, a series of 23 new dithiocarbamate‐methylsulfonyl derivatives were synthesized and their CA enzyme inhibitory activities were investigated. The inhibition potentials of the obtained compounds against the human CA I and CA II enzymes were investigated by the in vitro enzyme isolation method. It is seen that the compounds show activity at the nanomolar level. Molecular docking studies of the compounds were carried out by in silico methods. The poses of compounds 2a, 2e, 2o, and 2t are presented.

Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development

Abstract: Since June 2018, thousands of drug products from around the world had to be recalled due to the unexpected presence of nitrosamines (NAs). Starting with the pharmaceutical group of sartans, antidiabetic drugs, antihistamines, and antibiotics also became the subject of investigation. The occurrence of NAs has shown that pharmaceutical companies and regulatory agencies did not focus on these substances in the past during drug development. In this study, we incorporated a nitrosation assay procedure into high‐resolution supercritical fluid chromatography (SFC)–mass spectrometry screening to test the potential of direct nitrosation of active pharmaceutical ingredients (APIs). The forced degradation study was performed with a four‐fold molar excess of sodium nitrite, relative to the drug substance, at pH 3–4 for 4 h at 37°C. Chromatographic separation was performed on a porous graphitic carbon column by SFC. The mass analysis then focused on direct N‐nitrosation or N‐nitroso compounds (NOCs) formed after dealkylation. Substances (n = 67) from various pharmaceutical classes were evaluated and 49.3% of them formed NOCs, of which 21.2% have not yet been reported in the literature. In addition, for two APIs, which are known to form an unidentified NOC, the structure could be identified. A few substances also showed multiple NOCs and even N,N’‐dinitroso‐species. As NAs are carcinogens, they have to be eliminated or at least limited to prevent cancer in patients, who rely on these drugs. This study contributes a procedure that can be implemented in preapproval drug development and postapproval risk assessment to prevent unexpected findings in the future.

Oxadiazole: A highly versatile scaffold in drug discovery

Abstract: As a pharmacologically important heterocycle, oxadiazole paved the way to combat the problem associated with the confluence of many commercially available drugs with different pharmacological profiles. The present review focuses on the potential applications of five‐membered heterocyclic oxadiazole derivatives, especially 1,2,4‐oxadiazole, 1,2,5‐oxadiazole, and 1,3,4‐oxadiazole, as therapeutic agents. Designing new hybrid molecules containing the oxadiazole moiety is a better solution for the development of new drug molecules. The designed molecules may accumulate a biological profile better than those of the drugs currently available on the market. The present review will guide the way for researchers in the field of medicinal chemistry to design new biologically active molecules based on the oxadiazole nucleus. Antitubercular, antimalarial, anti‐inflammatory, anti‐HIV, antibacterial, and anticancer activities of various oxadiazoles have been reviewed extensively here.

Discovery of novel pyrazole and pyrazolo[1,5‐a]pyrimidine derivatives as cyclooxygenase inhibitors (COX‐1 and COX‐2) using molecular modeling simulation

Abstract: Searching for effective and selective anti‐inflammatory agents, our study involved designing and synthesizing new pyrazole and pyrazolo[1,5‐a]pyrimidine derivatives 4–11. The structures of the synthesized derivatives were confirmed using different spectroscopic techniques. Virtual screening was achieved for the newly designed derivatives using in silico docking simulation inside the active sites of four proteins classified as two cyclooxygenases (COX)‐1 (PDB: 3KK6 and 4OIZ) and two COX‐2 (PBD: 1CX2 and 3LN1). Among them, six derivatives 4c, 5b, 6a, 7a, 7b, and 10b displayed the highest binding energy. These derivatives were evaluated for their in vitro COX‐1 and COX‐2 inhibitory activities and their selectivity indexes were calculated. Additionally, these derivatives displayed IC50 values ranging between 4.909 ± 0.25 and 57.53 ± 2.91 µM, and 3.289 ± 0.14 and 124 ± 5.32 µM, against COX‐1 and COX‐2, respectively. Furthermore, the tested derivatives were found to have selective inhibitory activity on the COX‐2 enzyme. Surprisingly, the two pyrazole derivatives 4c and 5b were found to be the most active, with IC50 values of 9.835 ± 0.50 and 4.909 ± 0.25 µM and 4.597 ± 0.20 and 3.289 ± 0.14 µM compared with meloxicam (1.879 ± 0.1 and 5.409 ± 0.23 µM) and celecoxib (5.439 ± 0.28 and 2.164 ± 0.09 µM) against COX‐1/‐2, respectively. Besides, two pyrazole derivatives, 4c and 5b, displayed a COX‐1/COX‐2 SI of 2.14 and 1.49. Computational techniques such as molecular docking, density function theory (DFT) calculation, and chemical absorption, distribution, metabolism, excretion, and toxicity evaluation were applied to explain the molecules’ binding mode, chemical nature, drug likeness, and toxicity prediction.

Ginkgo biloba in the management of the COVID‐19 severity

Abstract: The severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection is linked with inflammatory disorders and the development of oxidative stress in extreme cases. Therefore, anti‐inflammatory and antioxidant drugs may alleviate these complications. Ginkgo biloba L. folium extract (EGb) is a herbal medicine containing various active constituents. This review aims to provide a critical discussion on the potential role of EGb in the management of coronavirus disease 2019 (COVID‐19). The antiviral effect of EGb is mediated by different mechanisms, including blocking SARS‐CoV‐2 3‐chymotrypsin‐like protease that provides trans‐variant effectiveness. Moreover, EGb impedes the development of pulmonary inflammatory disorders through the diminution of neutrophil elastase activity, the release of proinflammatory cytokines, platelet aggregation, and thrombosis. Thus, EGb can attenuate the acute lung injury and acute respiratory distress syndrome in COVID‐19. In conclusion, EGb offers the potential of being used as adjuvant antiviral and symptomatic therapy. Nanosystems enabling targeted delivery, personalization, and booster of effects provide the opportunity for the use of EGb in modern phytotherapy.

Synthesis, characterization, and biological evaluation of some novel Schiff bases as potential metabolic enzyme inhibitors

Abstract: In this study, a series of novel Schiff base derivatives containing a pyrazolone ring (2a–e) were designed, successfully synthesized for the first time, and characterized by elemental analysis and some spectroscopic methods. These compounds were tested for their inhibitory activities on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and the human carbonic anhydrase isoenzymes I and II (hCA I and II). All synthesized molecules indicated significant inhibition effects with IC50 values ranging from 14.15 to 107.62 nM against these enzymes. Compound 2d showed the most potent inhibitory activity among the tested molecules toward AChE and BChE (IC50 = 15.07 and 14.15 nM) compared to the standard drug neostigmine. We determined that the IC50 values of the tested molecules ranged between 16.86 and 57.96 nM for hCA I and 15.24–46.21 nM for hCA II. As a consequence, we may say that some of the Schiff base derivatives may be used as potential drug candidates in later studies.

New 1,3,4‐oxadiazoles linked with the 1,2,3‐triazole moiety as antiproliferative agents targeting the EGFR tyrosine kinase

Abstract: A series of 1,3,4‐oxadiazole‐1,2,3‐triazole hybrids bearing different pharmacophoric moieties has been designed and synthesized. Their antiproliferative activity was evaluated against four human cancer cell lines (Panc‐1, MCF‐7, HT‐29, and A‐549) using the MTT (3‐(4,5‐dimethylthiazol‐2‐yl)−2,5‐diphenyltetrazolium bromide) assay. The preliminary activity test displayed that the most active compounds, 6d, 6e, and 8a–e, suppressed cancer cell growth (GI50 = 0.23–2.00 µM) comparably to erlotinib (GI50 = 0.06 µM). Compounds 6d, 6e, and 8a–e inhibited the epidermal growth factor receptor tyrosine kinase (EGFR‐TK) at IC50 = 0.11–0.73 µM, compared to erlotinib (IC50 = 0.08 ± 0.04 µM). The apoptotic mechanism revealed that the most active hybrid 8d induced expression levels of caspase‐3, caspase‐9, and cytochrome‐c in the human cancer cell line Panc‐1 by 7.80‐, 19.30‐, and 13‐fold higher than doxorubicin. Also, 8d increased the Bax level by 40‐fold than doxorubicin, along with decreasing Bcl‐2 levels by 6.3‐fold. Cell cycle analysis after treatment of Panc‐1 cells with hybrid 8d revealed a high proportion of cell accumulation (41.53%) in the pre‐G1 phase, indicating cell cycle arrest at the G1 transition. Computational docking of the 8d and 8e hybrids with the EGFR binding site revealed their ability to bind with EGFR similar to erlotinib. Finally, in silico absorption, distribution, metabolism, and excretion/pharmacokinetic studies for the most active hybrids are discussed.

Design, synthesis, and biological evaluation of isatin‐indole‐3‐carboxaldehyde hybrids as a new class of xanthine oxidase inhibitors

Abstract: A novel series of triazole‐linked isatin‐indole‐3‐carboxaldehyde hybrids based on the febuxostat skeleton and its binding site interactions were rationally designed and synthesized as potential xanthine oxidase inhibitors. Among the synthesized hybrids, A19 showed the most potent xanthine oxidase inhibition (IC50 = 0.37 µM) with the mixed‐type inhibitory scenario. Structure–activity relationship studies revealed that methoxy (OCH3) substitution on position 5 of the isatin nucleus and a two‐carbon distance between isatin and the triazole moiety is most tolerable for the inhibitory potential. Various binding interactions of A19 with the binding site of xanthine oxidase are also streamlined by molecular docking studies, which showcase the favorable binding pattern for xanthine oxidase inhibition by the hybrid. Furthermore, molecular dynamic studies were performed that suggest the stability of the enzyme–hybrid complex. Overall, the study suggests that hybrid A19 can act as an effective hit lead for further development of potent xanthine oxidase inhibitors.

Cinnamic acid hybrids as anticancer agents: A mini‐review

Abstract: Cancer, as a long‐lasting and dramatic disease, affects almost one‐third of human beings globally. Chemotherapeutics play an important role in cancer treatment, but multidrug resistance and severe adverse effects have already become the main causes of failure in tumor chemotherapy. Therefore, it is an urgent need to develop novel chemotherapeutics. Cinnamic acid contains a ubiquitous α,β‐unsaturated acid moiety presenting potential therapeutic effects in the treatment of cancer as these derivatives could act on cancer cells by diverse mechanisms of action. Accordingly, cinnamic acid derivatives are critical scaffolds in discovering novel anticancer agents. This review provides a comprehensive overview of cinnamic acid hybrids as anticancer agents. The structure–activity relationship, as well as the mechanisms of action, are also discussed, covering articles published from 2012 to 2021.

Design, synthesis, and characterization of PROTACs targeting the androgen receptor in prostate and lung cancer models

Abstract: Although the androgen receptor (AR) is a validated target for the treatment of prostate cancer, resistance to antiandrogens necessitates the development of new therapeutic modalities. Exploiting the ubiquitin‐proteasome system with proteolysis‐targeting chimeras (PROTACs) has become a practical approach to degrade specific proteins and thus to extend the portfolio of small molecules used for the treatment of a broader spectrum of diseases. Herein, we present three subgroups of enzalutamide‐based PROTACs in which only the exit vector was modified. By recruiting cereblon, we were able to demonstrate the potent degradation of AR in lung cancer cells. Furthermore, the initial evaluation enabled the design of an optimized PROTAC with a rigid linker that degraded AR with a DC50 value in the nanomolar range. These results provide novel AR‐directed PROTACs and a clear rationale for further investigating AR involvement in lung cancer models.

Microwave‐assisted N‐alkylation of amines with alcohols catalyzed by MnCl2: Anticancer, docking, and DFT studies

Abstract: A new protocol for the N‐alkylation of amines with alcohols for the synthesis of tertiary amines in the presence of MnCl2 as a catalyst, under microwave conditions, is described. The advantages of this protocol include stable reaction profiles, a wide substrate variety, excellent yields, low cost, high yields, and easy workup conditions. The anticancer efficacy of all the synthesized compounds was tested in vitro against various cancer cell lines, such as MCF‐7, MDA‐MB‐231 (human breast), HT‐29, HCT 116 (colon cancer), A549 (human lung carcinoma), and Vero cells. Among the screened compounds, 3e, 3h, and 3i demonstrated potent anticancer activity, with compound 3h surpassing the reference drug cisplatin against A549, MCF7, MDA‐MB‐231, and HCT116 cancer cells. The introduction of an electron‐withdrawing group on the phenyl ring resulted in increased anticancer activity. The most potent compounds, 3e, 3h, and 3i, were tested against VEGFR‐2, HER2, and EGFR in multikinase inhibition assays, with compounds 3h and 3i showing improved potency against the HER2 kinase. The compounds formed two H‐bonds with amino acids, indicating that they had a high affinity for the target HER2 kinase (PDB ID: 3RCD), according to the docking analysis. The absorption, distribution, metabolism, excretion, and toxicity properties of the optimized analogs were also assessed in vitro, enabling the discovery of promising anticancer agents. Finally, the B3LYP level was used to measure density functional theory geometry optimization and the related quantum parameters for the active compounds.

Isatin thiazoles as antidiabetic: Synthesis, in vitro enzyme inhibitory activities, kinetics, and in silico studies

Abstract: Diabetes mellitus is one of the most prevalent diseases nowadays. Several marketed drugs are available for the cure and treatment of diabetes, but there is still a dire need of introducing compatible drug molecules with lesser side effects. The current study is based on the synthesis of isatin thiazole derivatives 4–30 via the Hantzsch reaction. The synthetic compounds were characterized using different spectroscopic techniques and evaluated for their α‐amylase and α‐glucosidase inhibition potential. Of 27 isatin thiazoles, five (4, 5, 10, 12, and 16) displayed good activities against the α‐amylase enzyme with IC50 values in the range of 22.22 ± 0.02–27.01 ± 0.06 µM, and for α‐glucosidase, the IC50 values of these compounds were in the range of 20.76 ± 0.17–27.76 ± 0.17 µM, respectively. The binding interactions of the active molecules within the active site of enzymes were studied with the help of molecular docking studies. In addition, kinetic studies were carried out to examine the mechanism of action of the synthetic molecules as well. Compounds 3a, 4, 5, 10, 12, and 16 were also examined for their cytotoxic effect and were found to be noncytotoxic. Thus, several molecules were identified as good antihyperglycemic agents, which can be further modified to enhance inhibition ability and to find the lead molecule that can act as a potential antidiabetic agent.

Design, synthesis, cytotoxicity, and molecular docking studies of novel thiazolyl–hydrazone derivatives as histone lysine acetyl‐transferase inhibitors and apoptosis inducers

Abstract: Compounds containing both thiazole and arylsulfone moieties are recognized for their high biological activity and ability to fight a variety of ailments. Thus, in this context, new derivatives of (thiazol‐2‐yl)hydrazone with an arylsulfone moiety were synthesized as CPTH2 analogs with potent anti‐histone lysine acetyl‐transferase activity. Compounds 3, 4, 10b, and 11b showed an excellent inhibitory effect on P300 (E1A‐associated protein p300), compared to CPTH2. Among all the tested derivatives, compound 10b revealed the highest activity against both P300 and pCAF. In addition, the new hits were tested for anticancer efficacy against two leukemia cell lines. Most of them showed a moderate to potent antitumor effect on the k562 and CCRF‐CEM cell lines. Interestingly, the activity of compound 10b against the k562 cell line was found to be higher than that of CPTH2. Furthermore, it showed a good safety profile, better than CPTH2 on normal cells. Molecular docking analysis was carried out to reveal the crucial binding contacts in the inhibition of the P300 and pCAF enzymes.

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure–activity relationship, and mechanisms of action (2019–2021)

Abstract: Cancer, characterized by a deregulation of the cell cycle which mainly results in a progressive loss of cellular differentiation and uncontrolled cellular growth, remains a prominent cause of death across the world. Almost all currently available anticancer agents used in clinical practice have developed multidrug resistance, creating an urgent need to develop novel chemotherapeutics. Benzimidazole derivatives could exert anticancer properties through diverse mechanisms, inclusive of the disruption of microtubule polymerization, the induction of apoptosis, cell cycle (G2/M) arrest, antiangiogenesis, and blockage of glucose transport. Moreover, several benzimidazole‐based agents have already been approved for the treatment of cancers. Hence, benzimidazole derivatives are useful scaffolds for the development of novel anticancer agents. In particular, benzimidazole hybrids could exert dual or multiple antiproliferative activities and had the potential to overcome drug resistance, demonstrating the potential of benzimidazole hybrids as potential prototypes for clinical deployment in the control and eradication of cancers. The purpose of the present review article is to provide a comprehensive landscape of benzimidazole hybrids as potential anticancer agents, and the structure–activity relationship as well as mechanisms of action are also discussed to facilitate the further rational design of more effective candidates, covering articles published from 2019 to 2021.

The current scenario on anticancer activity of artemisinin metal complexes, hybrids, and dimers

Abstract: Cancer, the most significant cause of morbidity and mortality, has already posed a heavy burden on health care systems globally. In recent years, cancer treatment has made a significant breakthrough, but cancer cells inevitably acquire resistance, and the efficacy of the treatment is greatly reduced as the tumor progresses. To overcome the above issues, novel chemotherapeutics are needed urgently. Artemisinin and its derivatives—sesquiterpene lactone compounds possessing a unique peroxy bridge moiety—exhibit excellent safety and tolerability profiles. Mechanistically, artemisinin derivatives can promote cancer cell apoptosis, induce cell cycle arrest and autophagy, and inhibit cancer cell invasion and migration. Accordingly, artemisinin derivatives demonstrate promising anticancer efficacy both in vitro and in vivo, and even in clinical Phase I/II trials. The purpose of the present review article is to provide an emphasis on the current scenario (January 2017–January 2022) of artemisinin derivatives with potential anticancer activity, inclusive of artemisinin metal complexes, hybrids, and dimers. The structure–activity relationships and mechanisms of action are also discussed to facilitate the further rational design of more effective candidates.

Design, synthesis, in silico ADMET, docking, and antiproliferative evaluations of [1,2,4]triazolo[4,3‐c]quinazolines as classical DNA intercalators

Abstract: Eleven novel [1,2,4]triazolo[4,3‐c]quinazolines were designed, synthesized, and evaluated against HepG2 and HCT‐116 cells. The molecular design was performed to investigate the binding mode of the proposed compounds with the DNA active site. The data obtained from biological testing highly correlated with that obtained from molecular modeling. HCT‐116 was found to be the most sensitive cell line to the influence of the new derivatives. In particular, compounds 6f and 6e were found to be the most potent derivatives over all the tested compounds against the two HepG2 and HCT116 cancer cell lines, with IC50 = 23.44 ± 2.9, 12.63 ± 1.2, and 25.80 ± 2.1, and 14.32 ± 1.5 µM, respectively. Although compounds 6f and 6e displayed less activity than doxorubicin (IC50 = 7.94 ± 0.6 and 8.07 ± 0.8 µM, respectively), both could be useful as a template for future design, optimization, and investigation to produce more potent anticancer analogs. The most active derivatives 6a, 6c, 6e, and 6f were evaluated for their DNA‐binding activities. Compound 6f displayed the highest binding affinity. This compound potently intercalates DNA at a decreased IC50 value (54.08 µM). Compounds 6a, 6c, and 6e exhibited good DNA‐binding affinities, with IC50 values of 79.35, 84.08, and 59.35 µM, respectively. Furthermore, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles were calculated for the four most active compounds in comparison to doxorubicin as a reference drug. Our derivatives 6a, 6c, 6e, and 6f displayed very good in‐silico‐predicted ADMET profiles. Doxorubicin violates three of Lipinski's rules, our derivatives 6a, 6c, 6e, and 6f do not violate any rule.

Some phenolic natural compounds as carbonic anhydrase inhibitors: An in vitro and in silico study

Abstract: This paper presents experimental and molecular docking studies on the inhibitory effects of tyrosol, hydroxytyrosol, luteolin, diosmetin, caffeic acid, luteolin 7‐O‐glycoside, and apigenin 7‐O‐glycoside from olive (Olea europaea L.) leaf against human carbonic anhydrase (hCA, E.C.4.2.1.1) isozymes I and II. After these isozymes were separately purified, their activities were determined using the esterase activity. IC50 values for hCA I and II were calculated as 2.02–11.38 µM and 2.23–9.05 µM, respectively. The compounds were identified as CA inhibitors, with Ki values in the ranges of 1.66–9.17 µM for the hCA I isozyme and 1.49–14.21 µM for hCA II. The inhibitory effects of these natural compounds were also compared to acetazolamide, which is a potent inhibitor of both CA isozymes. Our results may contribute to the synthesis of new CA inhibitors and pave the way for new drug design in the treatment of a number of diseases including cancer, obesity, diabetes, and glaucoma.

Revealing the role of the benzyloxy pharmacophore in the design of a new class of monoamine oxidase‐B inhibitors

Abstract: The conceptual layout of monoamine oxidase (MAO) inhibitors has been modified to explore their potential biological application in the case of neurological disorders for the time being. The current review article is an effort to display the summation of innovative conceptual prospects of MAO inhibitors and their intriguing chemistry and bioactivity. Based on this scenario, we emphasize the pivotal role of the benzyloxy moiety attached to scaffolds like oxadiazolones, indolalkylamines, safinamide, caffeine, benzofurans, α‐tetralones, β‐nitrostyrene, benzoquinones, coumarins, indoles, chromones, and chromanone analogs, while acting as an MAO inhibitor.

Tandem synthesis, cytotoxicity, and in silico study of new 1,3,4‐oxadiazoles as potential thymidylate synthase inhibitors

Abstract: A new series of pyrrole‐linked mono‐ and bis(1,3,4‐oxadiazole) hybrids, attached to various arene units, was prepared using a two‐step tandem protocol. Therefore, a benzohydrazide derivative was condensed with the appropriate aldehydes in ethanol at 80°C for 60–150 min to give the corresponding N‐(benzoylhydrazones). Without isolation, the previous intermediates underwent intramolecular oxidative cyclization in dimethyl sulfoxide at 180°C for 90–200 min in the presence of chloramine trihydrate to afford the target hybrids. The cytotoxicity of all hybrids was examined in vitro against the MCF‐7, HEPG2, and Caco2 cell lines. Arene‐linked hybrids 4i and 4j, attached to p‐nitro and p‐acetoxy units, were the most potent ones, with IC50 values ranging from 5.47 to 8.80 and 12.75 to 21.22 μM, respectively, when tested on the above cell lines. At the tested concentrations of 5 and 7.5 μM, hybrid 4i inhibited thymidylate synthase (TS) with the best inhibition percentages of 72.3 and 91.3, whereas hybrid 4j displayed comparable inhibitory activity to the reference pemetrexed. Hybrid 4j had inhibition percentages of 62.7 and 82.6, whereas pemetrexed had inhibition percentages of 59.2 and 80.2, respectively. The capability of hybrids 4i and 4j as potential TS inhibitors is supported by molecular docking studies, while SwissADME predicts their efficacy as drug‐like scaffolds.

3D‐QSAR and scaffold hopping based designing of benzo[d]ox‐azol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation

Abstract: Aldehyde dehydrogenase 1 (ALDH1A1), an oxidoreductase class of enzymes, is overexpressed in various types of cancer cell lines and is the major cause of resistance to the Food and Drug Administration (FDA)‐approved drug, cyclophosphamide (CP). In cancer conditions, CP undergoes a sequence of biotransformations to form an active metabolite, aldophosphamide, which further biotransforms to its putative cytotoxic metabolite, phosphoramide mustard. However, in resistant cancer conditions, aldophosphamide is converted into its inactive metabolite, carboxyphosphamide, via oxidation with ALDH1A1. Herein, to address the issue of ALDH1A1 mediated CP resistance, we report a series of benzo[d]oxazol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective ALDH1A1 inhibitors. These inhibitors were designed using a validated 3D‐quantitative structure activity relationship (3D‐QSAR) model coupled with scaffold hopping. The 3D‐QSAR model was developed using reported indole‐2,3‐diones based ALDH1A1 inhibitors, which provided field points in terms of electrostatic, van der Waals and hydrophobic potentials required for selectively inhibiting ALDH1A1. The most selective indole‐2,3‐diones‐based compound, that is, cmp 3, was further considered for scaffold hopping. Two top‐ranked bioisosteres, that is, benzo[d]oxazol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one, were selected for designing new inhibitors by considering the field pattern of 3D‐QSAR. All designed molecules were mapped perfectly on the 3D‐QSAR model and found to be predictive with good inhibitory potency (pIC50 range: 7.5–6.8). Molecular docking was carried out for each designed molecule to identify key interactions that are required for ALDH1A1 inhibition and to authenticate the 3D‐QSAR result. The top five inhibitor‐ALDH1A1 complexes were also submitted for molecular dynamics simulations to access their stability. In vitro enzyme assays of 21 compounds suggested that these compounds are selective toward ALDH1A1 over the other two isoforms, that is, ALDH2 and ALDH3A1. All the compounds were found to be at least three and two times more selective toward ALDH1A1 over ALDH2 and ALDH3A1, respectively. All the compounds showed an IC50 value in the range of 0.02–0.80 μM, which indicates the potential for these to be developed as adjuvant therapy for CP resistance.

Biological functions of kojic acid and its derivatives in medicine, cosmetics, and food industry: Insights into health aspects

Abstract: This review traces the road leading to the demonstration of a variety of kojic acid chemical and biological properties. It illustrates the biological effects of several synthetic kojic acid derivatives. Besides the main capability of kojic acid to inhibit the activity of tyrosinase in melanin synthesis, the focus is also on antibacterial, antifungal, antiproliferative, anti‐inflammatory, and other biological activities of kojic acid derivatives, which may be applicable in medicine. Kojic acid derivatives manifest antiparasitic effects and its metal complexes may serve as potential radioprotective agents. Several kojic acid derivatives exert antidiabetic therapeutic potential as nuclear peroxisome proliferator‐activated receptor alpha/gamma dual agonists. Kojic acid derivatives show pancreatic lipase inhibitor properties and some of its derivatives are cognate ligands for the histamine H3 receptor. Recently, “KojoTacrines” were reported as novel perspective preparations for the therapy of Alzheimer's disease. Kojic acid derivatives possess insecticidal or pesticidal activity, and they are powerful chelators, able to form iron(III) containing nanocomposites, as well. Toxicology and health aspects of products containing kojic acid produced by the cosmetic, health care, or food industry are summarized. Kojic acid thus represents a highly attractive molecule containing a skeleton that allows the synthesis of new kojic acid derivatives to create a novel class of effective and specific pharmaceutical preparations.

A comprehensive review of recent advances in the biological activities of 1,2,4‐oxadiazoles

Abstract: Nitrogen heterocycles play an essential role in medication development. The 1,2,4‐oxadiazole heterocycle has been extensively studied, yielding a large variety of molecules with varied biological functions. The 1,2,4‐oxadiazole shows bioisosteric equivalency with ester and amide moieties. In recent years, the 1,2,4‐oxadiazole nucleus has received a lot of attention in medicinal chemistry. It was thought to be a pharmacophore component in the production of biologically intriguing drugs. This review presents a comprehensive overview of the recent achievements in the biological activities of 1,2,4‐oxadiazoles as potential antimicrobial, anticancer, anti‐inflammatory, neuroprotective, and antidiabetic agents. The structure–activity relationship and mechanisms of action are also reviewed.

New 4‐phenylpiperazine‐carbodithioate‐N‐phenylacetamide hybrids: Synthesis, in vitro and in silico evaluations against cholinesterase and α‐glucosidase enzymes

Abstract: A series of novel 4‐phenylpiperazine‐carbodithioate‐N‐phenylacetamide hybrids (6a–n) was designed, synthesized, and evaluated for their in vitro inhibitory activity against the metabolic enzymes, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α‐glucosidase. The obtained results showed that most of the synthesized compounds exhibited high to good anti‐AChE and anti‐BChE activity in the range of nanomolar concentrations in comparison to tacrine as a positive control. Molecular modeling of the most potent compounds 6e and 6i demonstrated that these compounds interacted with important residues of the AChE and BChE active sites. Moreover, all the newly synthesized compounds 6a–n had significant Ki values against α‐glucosidase when compared with the positive control acarbose. Representatively, N‐2‐fluorophenylacetamide derivative 6l, with a Ki value of 0.98 nM as the most potent compound, was 126 times more potent than acarbose with a Ki value of 123.70 nM. This compound also fitted in the α‐glucosidase active site and interacted with key residues. An in silico study of the druglikeness/absorption, distribution, metabolism, and excretion (ADME)/toxicity profile of the selected compounds 6e, 6i, and 6l predicts that these compounds are drug‐like and have the appropriate properties in terms of ADME and toxicity.

Triazoloquinazoline derived classical DNA intercalators: Design, synthesis, in silico ADME profile, docking, and antiproliferative evaluations

Abstract: Thirteen novel [1,2,4]triazolo[4,3‐c]quinazoline derivatives as DNA intercalators were synthesized and their anticancer activities evaluated against HepG2 and HCT‐116 cells. A docking study was carried out to explore how the new derivatives bind to active sites of DNA. The docking data were highly interrelated with that of biological testing. The HCT‐116 cell line was the most sensitive one to the effect of the new derivatives. Compound 7c exhibited the highest anticancer activities against both the HepG2 and HCT116 cancer cell lines. Despite this compound displaying less activity than doxorubicin, it could be useful as a template for future manipulation, optimization, and investigation to produce other analogs with potential activity. The most active derivatives, 7c, 7b, and 7a were evaluated as DNA binders. Compound 7c displayed the highest binding affinity. Furthermore, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile was calculated for the four most active compounds in comparison to doxorubicin as reference drug. Our derivatives 7a, 7b, and 7c displayed a very good calculated ADMET profile in comparison to doxorubicin.

Discovery of oxindole‐based FLT3 inhibitors as a promising therapeutic lead for acute myeloid leukemia carrying the oncogenic ITD mutation

Abstract: FMS‐like tyrosine kinase 3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) patients. In the current study, the oxindole chemotype is employed as a structural motif for the design of new FLT3 inhibitors as potential hits for AML irradiation. Cell‐based screening was performed with 18 oxindole derivatives and 5a–c inhibited 68%–73% and 83%–91% of internal tandem duplication (ITD)‐mutated MV4‐11 cell growth for 48‐ and 72‐h treatments while only 0%–2% and 27%–39% in wild‐type THP‐1 cells. The most potent compound 5a inhibited MV4‐11 cells with IC50 of 4.3 µM at 72 h while it was 8.7 µM in THP‐1 cells, thus showing two‐fold selective inhibition against the oncogenic ITD mutation. The ability of 5a to modulate cell death was examined. High‐throughput protein profiling revealed low levels of the growth factors IGFBP‐2 and ‐4 with the blockage of various apoptotic inhibitors such as Survivin. p21 with cellular stress mechanisms was characterized by increased expression of HSP proteins along with TNF‐β. Mechanistically, compounds 5a and 5b inhibited FLT3 kinase with IC50 values of 2.49 and 1.45 µM, respectively. Theoretical docking studies supported the compounds' ability to bind to the FLT3 ATP binding site with the formation of highly stable complexes as evidenced by molecular dynamics simulations. The designed compounds also provide suitable drug candidates with no violation of drug likeability rules.

Cyanopropyl functionalized benzimidazolium salts and their silver N‐heterocyclic carbene complexes: Synthesis, antimicrobial activity, and theoretical analysis

Abstract: The reaction of N‐substituted benzimidazole with 4‐bromobutyronitrile gives the corresponding benzimidazolium salts as N‐heterocyclic carbene (NHC) precursors. Silver(I) carbene complexes are synthesized by the reaction of the corresponding benzimidazolium salts with Ag2O in dichloromethane. These new NHC precursors and Ag–NHC complexes were characterized by spectroscopy techniques and also screened for their antibacterial activities against the standard bacterial strains Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Staphylococcus aureus, methicillin‐resistant Staphylococcus aureus, and Enterococcus faecalis, and the standard fungal strains Candida albicans and Candida glabrata, and promising results were achieved. The compounds were also analyzed by density functional theory (DFT)/time‐dependent DFT and docking methods.

Thiophene‐containing compounds with antimicrobial activity

Abstract: Thiophene, as a member of the group of five‐membered heterocycles containing one heteroatom, is one of the simplest heterocyclic systems. Many synthetic strategies allow the accurate positioning of various functionalities onto the thiophene ring. This review provides a comprehensive, systematic and detailed account of the developments in the field of antimicrobial compounds featuring at least one thiophene ring in their structure, over the last decade.

Green synthesis of pregabalin‐stabilized gold nanoclusters and their applications in sensing and drug release

Abstract: This is the first report on the simple preparation of gold nanoclusters stabilized with pregabalin (PREG) as a capping and reducing agent. PREG is an active pharmaceutical ingredient of the commercially available drug “Lyrica” used to treat different diseases like epilepsy and anxiety. PREG has never been used before in the synthesis of any nanoparticles or nanoclusters. The prepared gold nanoclusters (PREG‐stabilized gold nanoclusters [PREG‐AuNCs]) have blue fluorescence with excitation/emission at 365/425 nm, respectively. The reaction conditions were optimized for the synthesis of the as‐prepared AuNCs. Different tools were used for the characterization of the synthesized nanoclusters in terms of size and surface properties. The PREG‐AuNCs were exploited as a sensitive and selective fluorescent nanosensor for Cu2+ detection. The quenching of AuNC fluorescence intensity in the presence of Cu2+ is due to the aggregation‐induced fluorescence quenching mechanism. The detection limit of Cu2+ ions was found to be 1.11 × 10−7 M. The selectivity of the PREG‐AuNCs was studied and proved to be excellent. The drug entrapment efficacy and in vitro drug diffusion studies along with drug release kinetics helped to understand more about the pharmaceutical approaches of PREG‐AuNCs. Moreover, we think that PREG‐AuNCs open new opportunities as a promising candidate material for drug delivery systems and medical applications.

New quinoxalin‐2(1H)‐one‐derived VEGFR‐2 inhibitors: Design, synthesis, in vitro anticancer evaluations, in silico ADMET, and docking studies

Abstract: More than 70% of cancer patients who are treated with chemotherapeutics do not show a durable response. As part of the global plan seeking new effective chemotherapeutics, here, we report the synthesis and in vitro and computational studies of new lenvatinib and sorafenib analog quinoxalines as vascular endothelial growth factor receptor II (VEGFR‐2) tyrosine kinase inhibitors. The central quinolone and pyridine moieties of the Food and Drug Administration‐approved anticancer agents lenvatinib and sorafenib were replaced with the versatile quinoxaline scaffold that has been exploited for developing potent cytotoxic agents. With some minor structural optimizations, all the other pharmacophoric features of lenvatinib and sorafenib were maintained. Accordingly, three new sets of quinoxalines were synthesized to evaluate their activity against liver, colorectal, and breast malignancies. The results obtained in the in vitro cytotoxicity evaluation study revealed the superior activity of three derivatives (20, 25, and 29) compared with that of doxorubicin and sorafenib. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling and docking of 20, 25, and 29 into the VEGFR‐2 receptor were also performed. Results of in silico studies showed the potential of the designed compounds to bind effectively with a number of key residues. The obtained in vitro cytotoxic activity and ADMET profiles of compounds 20, 25, and 29 suggested that they should be subjected to further structural optimizations to develop new candidates in cancer treatment protocols.

Cardioprotective effect of silymarin nanoemulsion on 5‐fluorouracil‐induced cardiotoxicity in rats

Abstract: 5‐Fluorouracil (5‐FU)‐associated cardiotoxicity has been ranked as the second most common cause of cardiotoxicity induced by chemotherapeutic drugs after anthracyclines. In the present study, we investigated the protective impacts of silymarin (SIL) and silymarin nanoemulsion (SLN) against cardiotoxicity caused by 5‐FU in rats. Thirty male Wistar rats were divided into six groups as follows: control, SLN (5 mg/kg), SIL (5 mg/kg), 5‐FU + SLN, 5‐FU + SIL, and 5‐FU. Cardiotoxicity was induced by a single intraperitoneal injection of 5‐FU (100 mg/kg). The control group received an intraperitoneal injection (ip) of normal saline and the treatment groups received ips of SIL and SLN for 14 days. 5‐FU resulted in significant cardiotoxicity, represented by an increase in the serum levels of cardiac enzymes and malondialdehyde, as well as cyclooxygenase‐2 (COX‐2) and tumor necrosis factor‐α (TNF‐α) expression, and histopathological degeneration. 5‐FU treatment also induced a decrease in body weight, total antioxidant capacity (TAC), and catalase values. Evaluation of electrocardiographic parameters in 5‐FU‐treated rats showed increases in the ST segment, QRS duration, and RR interval. Treatment with SIL and SLN reduced oxidative stress, cardiac enzymes, histopathological degeneration, and the expression of TNF‐α and COX‐2 in cardiac tissue. Our results demonstrated that treatment with SIL and SLN significantly improved cardiotoxicity induced by 5‐FU in rats.