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α-Glucosidase inhibition is an approved treatment for type 2 diabetes mellitus (T2DM). In an attempt to develop novel anti-α-glucosidase agents, two series of substituted imidazo[1,2-c]quinazolines, namely 6a–c and 11a–o, were synthesized using a simple, straightforward synthetic routes. These compounds were thoroughly characterized by IR, 1H and 13C NMR spectroscopy, as well as mass spectrometry and elemental analysis. Subsequently, the inhibitory activities of these compounds were evaluated against Saccharomyces cerevisiae α-glucosidase. In present study, acarbose was utilized as a positive control. These imidazoquinazolines exhibited excellent to great inhibitory potencies with IC50 values ranging from 12.44 ± 0.38 μM to 308.33 ± 0.06 μM, which were several times more potent than standard drug with IC50 value of 750.0 ± 1.5 μM. Representatively, compound 11j showed remarkable anti-α-glucosidase potency with IC50 = 12.44 ± 0.38 μM, which was 60.3 times more potent than positive control acarbose. To explore the potential inhibition mechanism, further evaluations including kinetic analysis, circular dichroism, fluorescence spectroscopy, and thermodynamic profile were carried out for the most potent compound 11j. Moreover, molecular docking studies and in silico ADME prediction for all imidazoquinazolines 6a–c and 11a–o were performed to reveal their important binding interactions, as well as their physicochemical and drug-likeness properties, respectively. [ABSTRACT FROM AUTHOR]

In an attempt to find novel, potent α-glucosidase inhibitors, a library of poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag have been synthesized through heating a mixture of 2-aminobenzimidazoles 1 and α-azidochalcone 2 under the mild conditions. This efficient, facile protocol has been resulted into the desirable compounds with a wide substrate scope in good to excellent yields. Afterwards, their inhibitory activities against yeast α-glucosidase enzyme were investigated. Showing IC50 values ranging from 16.4 ± 0.36 µM to 297.0 ± 1.2 µM confirmed their excellent potency to inhibit α-glucosidase which encouraged us to perform further studies on α-glucosidase enzymes obtained from rat as a mammal source. Among various synthesized 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines, compound 3k exhibited the highest potency against both Saccharomyces cerevisiae α-glucosidase (IC50 = 16.4 ± 0.36 μM) and rat small intestine α-glucosidase (IC50 = 45.0 ± 8.2 μM). Moreover, the role of amine moiety on the observed activity was studied through substituting with chlorine and hydrogen resulted into a considerable deterioration on the inhibitory activity. Kinetic study and molecular docking study have confirmed the in-vitro results. [ABSTRACT FROM AUTHOR]

[Display omitted] • The pharmaceutical significance of imidazopyridines is described. • The importance of kinases in cellular processes and their structures are presented. • The role of kinases in the cancer treatment is explained. • The comprehensive review about imidazopyridines as kinase inhibitors are provided. • The substantial structural features and interactions of imidazopyridines against these kinases are thoroughly described. Considering the fundamental role of protein kinases in the mechanism of protein phosphorylation in critical cellular processes, their dysregulation, especially in cancers, has underscored their therapeutic relevance. Imidazopyridines represent versatile scaffolds found in abundant bioactive compounds. Given their structural features, imidazopyridines have possessed pivotal potency to interact with different protein kinases, inspiring researchers to carry out numerous structural variations. In this comprehensive review, we encompass an extensive survey of the design and biological evaluations of imidazopyridine-based small molecules as potential agents targeting diverse kinases for anticancer applications. We describe the structural elements critical to inhibitory potency, elucidating their key structure–activity relationships (SAR) and mode of actions, where available. We classify these compounds into two groups: Serine/threonine and Tyrosine inhibitors. By highlighting the promising role of imidazopyridines in kinase inhibition, we aim to facilitate the design and development of more effective, targeted compounds for cancer treatment. [ABSTRACT FROM AUTHOR]

In an attempt to find novel α-glucosidase inhibitors, an efficient, straightforward reaction to synthesize a library of fully substituted 6-amino-pyrazolo[1,5-a]pyrimidines 3 has been investigated. Heating a mixture of α-azidochalcones 1 and 3-aminopyrazoles 2 under the mild condition afforded desired compounds with a large substrate scope in good to excellent yields. All obtained products were evaluated as α-glucosidase inhibitors and exhibited excellent potency with IC50 values ranging from 15.2 ± 0.4 µM to 201.3 ± 4.2 µM. Among them, compound 3d was around 50-fold more potent than acarbose (IC50 = 750.0 ± 1.5 µM) as standard inhibitor. Regarding product structures, kinetic study and molecular docking were carried out for two of the most potent ones. [ABSTRACT FROM AUTHOR]

An efficient, one-pot and four-component protocol for the synthesis of new series of 2,3-disubstituted isoindolin-1-ones is performed and their Jack bean urease inhibitory activities are evaluated. All the obtained compounds 5a-p were found to be more active than the standard drugs thiourea and hydroxyurea. Molecular docking studies of these compounds were also performed that verified the results form in vitro tests. • Isoindolin-1-ones as new urease inhibitors. • Docking studies and in-silico ADME evaluation of derivatives. An efficient, one-pot and four-component synthesis of a new series of 2,3-disubstituted isoindolin-1-ones is described and their Jack bean urease inhibitory activities are evaluated. Heating a mixture of 1,1-bis(methylthio)-2-nitroethene, a 1,2-diamine, a 2-formylbenzoic acid and a primary amine in EtOH for 3.5 h afforded the corresponding 2,3-disubstituted isoindolin-1-ones in good to excellent yields. All sixteen synthesized isoindolin-1-one derivatives 5a–p showed urease inhibitory activity. Among them, 5c showed the most urease inhibitory activity (IC 50 = 10.07 ± 0.28 µM) being over 2-fold more potent than thiourea (IC 50 = 22.01 ± 0.10 µM) and 10-fold than hydroxyurea (IC 50 = 100.00 ± 0.02 µM) as the standard inhibitors, respectively. Also, results from molecular docking studies were in good agreement with those obtained from in vitro tests. [ABSTRACT FROM AUTHOR]

Graphical abstract A new series of fused carbazole–imidazoles 6a–w as potential α-glucosidase inhibitors was synthesized by one-pot two-step sequence. All the synthesized compounds were more active than acarbose as standard drug (IC 50 = 750.0 ± 1.5 µM) with IC 50 values in the range of 74.0 ± 0.7–298.3 ± 0.9 µM. Abstract Twenty three fused carbazole–imidazoles 6a–w were designed, synthesized, and screened as new α-glucosidase inhibitors. All the synthesized fused carbazole-imidazoles 6a-w were found to be more active than acarbose (IC 50 = 750.0 ± 1.5 µM) against yeast α-glucosidase with IC 50 values in the range of 74.0 ± 0.7–298.3 ± 0.9 µM. Kinetic study of the most potent compound 6v demonstrated that this compound is a competitive inhibitor for α-glucosidase (K i value = 75 µM). Furthermore, the in silico studies of the most potent compounds 6v and 6o confirmed that these compounds interacted with the key residues in the active site of α-glucosidase. [ABSTRACT FROM AUTHOR]

In this work, we report an efficient, one-pot and three-component synthesis of novel coumarin fused pyridine derivatives 4a–p. Heating the mixture of 4-hydroxycoumarins and ammonium acetate in DMF gave the corresponding 4-aminocoumarins, which subsequently went through Michael addition–cyclocondensation with α-azidochalcone derivatives to produce our desired products in high yields. The synthesized compounds 4a–p were evaluated for α-glucosidase inhibitory activity and all of them exhibited excellent in vitro yeast α-glucosidase inhibition with IC50 values ranging from 101.0 ± 2.0 to 227.3 ± 1.4 μM when compared with the standard drug acarbose (IC50 = 750.0 ± 1.5 μM). A kinetic study of the most potent compound 4i revealed that it inhibited α-glucosidase in a competitive mode. A docking study of the most active compounds 4i, 4h, and 4j was also performed. [ABSTRACT FROM AUTHOR]

A new series of 6-amino-pyrido[2,3-d]pyrimidine-2,4-dione derivatives 3a – 3s were prepared via a facile and efficient reaction from α -azidochalcones and 6-amiouracils. The reactions were performed under mild conditions to produce the corresponding compounds in good to excellent yields. Obtained derivatives 3a – 3s were evaluated for α-glucosidase inhibitory activity and all of them exhibited excellent in vitro yeast α -glucosidase inhibition with IC 50 values ranging from 78.0 ± 2.0 to 252.4 ± 1.0 μM. For example, the most active compound 3o was around 10-fold more potent than acarbose, a standard drug (IC 50  = 750.0 ± 1.5 μM). Kinetic study of compound 3o revealed that it inhibited α -glucosidase in a competitive mode. Molecular modeling studies of the most active compounds 3o , 3i , 3e and 3m were also performed. [ABSTRACT FROM AUTHOR]

A facile, mild and efficient procedure for the synthesis of fully substituted pyrazolo[3,4- b ]pyridin-5-amines is reported. A mixture of an α -azidochalcone, a 5-aminopyrazole and t -BuOK was stirred in DMF at ambient temperature for 5 min to afford the corresponding pyrazolo[3,4- b ]pyridin-5-amines in good to excellent yields. [ABSTRACT FROM AUTHOR]

Efficient and facile protocols for the preparation of highly functionalized 1 H -imidazoles and 5 H -pyrrolo[1,2- c ]imidazoles are described. Heating a mixture of an α-azidochalcones and N,N,N′,N′ -tetramethyl guanidine under neat conditions gave the corresponding 2,4,5-trisubstituted 1 H -imidazole via Michael addition-cyclization in excellent yields. Subsequently, the prepared 1 H -imidazoles undergo addition-Wittig reaction with acetylenic esters in presence of triphenylphosphine in dichloromethane to afford 5 H -pyrrolo[1,2- c ]imidazoles in high yields. [ABSTRACT FROM AUTHOR]

A one-pot and three-component reaction is described for the preparation of 2,3-disubstituted isoindolin-1-ones. Heating a mixture of 2-formylbenzoic acid, a cyclic six-membered β-dicarbonyl compound, and a benzylamine under solvent-free conditions afforded the title compounds in good to excellent yields. The generality of the reaction was shown by the use of various β-dicarbonyl compounds including 1,3-cyclohexadione, dimedone, Meldrum’s acid, N , N -dimethylbarbituric acid, and some benzylamine derivatives. [ABSTRACT FROM AUTHOR]

• A new series of dihydroindolizino[8,7- b ]indole derivatives 4a–r was synthesized as α -glucosidase inhibitors. • All synthesized compounds showed anti- α -glucosidase activity superior to standard drug (acarbose). • Compound 4o is the most active compound and a competitive inhibitor for α -glucosidase. • Compound 4o is around 7-fold more potent than acarbose. • Docking studies of the most active compounds 4o and 4 h were also performed. Eighteen dihydroindolizino[8,7- b ]indole derivatives 4a–r were designed, synthesized and evaluated as new α -glucosidase inhibitors. These derivatives were synthesized by an efficient one-pot two-step reaction under mild condition. All the synthesized compounds were found to be more active than the standard drug acarbose (IC 50 = 750.0 ± 1.5 µM) with IC 50 values in the range of 107.2 ± 1.0–275.4 ± 1.5 µM. Among the synthesized compounds, diethyl derivative 4o and dimethyl derivative 4 h exhibited the highest anti-α-glucosidase activities (IC 50 = 107.2 ± 1.0 and 118.0 ± 0.7 µM, respectively). Kinetic analysis of the compound 4o revealed that this compound is a competitive inhibitor for α -glucosidase with K i value of 113 µM. Furthermore, the docking study on the compounds 4o and 4 h revealed that these compounds interacted with the important residues in the active site of the homology model of α -glucosidase. [ABSTRACT FROM AUTHOR]

An efficient, one-pot and three-component synthesis of a new series of 2-acyl-3,4,6-triaryl-1,4-dihydropyrazines is described. This two-step strategy involves treatment of phenacyl bromides and anilines to give the nucleophilic substitution intermediate followed by Michael-addition-cyclization to α -azidochalcones to afford the title compounds in high yields. [ABSTRACT FROM AUTHOR]

Simply heating a mixture of β-dicarbonyl compounds, benzylamines, and acid (II) under solvent-free conditions gives isoindolines in good to excellent yields. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel series of imidazoquinazoline-based compounds were designed and synthesized. • Two compounds named 18a and 18o showed noticeable IC 50 values against PC3 and HeLa cell lines. • 18a and 18o demonstrated inhibitory potencies and selectivity toward EGFR (with EGFR-IC 50 values of 82.0 µM and 12.3 µM, respectively). • Western blot analysis of 18a and 18o revealed EGFR and ERK1/2 phosphorylation inhibition. • Computational studies including electrostatic potential map analysis, molecular docking, and non-covalent interaction studies were performed to complete this investigation. Tyrosine protein kinases (TKs) have been proved to play substantial roles on many cellular processes and their overexpression tend to be found in various types of cancers. Therefore, over recent decades, numerous tyrosine protein kinase inhibitors particularly epidermal growth factor receptor (EGFR) inhibitors have been introduced to treat cancer. Present study describes a novel series of imidazo[1,2- a ]quinazolines 18 as potential -inhibitors. These imidazoquinazolines (18a and 18o , in particular) had great anti-proliferative activities with IC 50 values in the micromolar (µM) range against PC3, HepG2, HeLa, and MDA-MB-231 comparing with Erlotinib as reference marketed drug. Further evaluations on some derivatives revealed their potential to induce apoptotic cell death and cell growth arrest at G0 phase of the cell cycle. Afterwards, the kinase assay on the most potent compounds 18a and 18o demonstrated their inhibitory potencies and selectivity toward EGFR (with EGFR-IC 50 values of 82.0 µM and 12.3 µM, respectively). Additionally, western blot analysis on these compounds 18a and 18o exhibited that they inhibited the phosphorylation of EGFR and its downstream molecule extracellular signal-regulated kinase (ERK1/2). However, the level of B-Actin phosphorylation was not changed. Finally, density functional theory calculations, docking study, and independent gradient model (IGM) were performed to illustrate the structure–activity relationship (SAR) and to assess the interactions between proteins and ligands. The results of molecular docking studies had great agreement with the obtained EGFR inhibitory results through in vitro evaluations. [ABSTRACT FROM AUTHOR]

The novel derivatives of tetrahydropyridothienopyrimidine-based compounds have been designed and efficiently synthesized with good yields through seven steps reaction. The anticancer activity of compounds 11a-y has been evaluated against MCF-7, PC-3, HEPG-2, SW-480, and HUVEC cell lines by MTT assay. The target compounds showed IC50 values between 2.81–29.6 μg/mL and were compared with sorafenib as a reference drug. Among them, compound 11n showed high cytotoxic activity against four out of five examined cell lines and was 14 times more selective against MRC5. The flow cytometric analysis confirmed the induction of apoptotic cell death by this compound against HUVEC and MCF-7 cells. In addition, 11n caused sub-G1 phase arrest in the cell cycle arrest. Besides, this compound induced anti-angiogenesis in CAM assay and increased the level of caspase-3 by 5.2 fold. The western-blot analysis of the most active compound, 11n, revealed the inhibition of VEGFR-2 phosphorylation. Molecular docking study also showed the important interactions for compound 11n. [ABSTRACT FROM AUTHOR]

Angiogenesis, the formation of new blood vessels from the existing vasculature, is pivotal in the migration, growth, and differentiation of endothelial cells in normal physiological conditions. In various types of tumour microenvironments, dysregulated angiogenesis plays a crucial role in supplying oxygen and nutrients to cancerous cells, leading to tumour size growth. VEGFR-2 tyrosine kinase has been extensively studied as a critical regulator of angiogenesis; thus, inhibition of VEGFR-2 has been widely used for cancer treatments in recent years. Quinazoline nucleus is a privileged and versatile scaffold with a broad range of pharmacological activity, especially in the field of tyrosine kinase inhibitors with more than twenty small molecule inhibitors approved by the US Food and Drug Administration in the last two decades. As of now, the U.S. FDA has approved eleven small chemical inhibitors of VEGFR-2 for various types of malignancies, with a prime example being vandetanib, a quinazoline derivative, which is a multi targeted kinase inhibitor used for the treatment of late-stage medullary thyroid cancer. Despite of prosperous discovery and development of VEGFR-2 down regulator drugs, there still exists limitations in clinical efficacy, adverse effects, a high rate of clinical discontinuation and drug resistance. Therefore, there is an urgent need for the design and synthesis of more selective and effective inhibitors to tackle these challenges. Through the gathering of this review, we have strived to broaden the extent of our view over the entire scope of quinazoline-based VEGFR-2 inhibitors. Herein, we give an overview of the importance and advancement status of reported structures, highlighting the SAR, biological evaluations and their binding modes. [Display omitted] • Inhibitors of VEGFR-2 tyrosine kinase have been widely used for cancer treatments. • Quinazoline nucleus is a privileged and versatile scaffold with a broad range of pharmacological activity. • Advancement status of reported quinazoline-based inhibitors targeting VEGFR-2 (SAR and biological evaluations are depicted). [ABSTRACT FROM AUTHOR]

In an attempt to find new potent cytotoxic compounds, several mono- and bis-pyrazolophthalazines 4a-m and 6a-h were synthesized through an efficient, one-pot, three- and pseudo five-component synthetic approach. All derivatives were evaluated for their in vitro cytotoxic activities against four human cancer cell lines of A549, HepG2, MCF-7, and HT29. Compound 4e showed low toxicity against normal cell lines (MRC-5 and MCF 10A, IC 50 > 200 µM) and excellent cytotoxic activity against A549 cell line with IC 50 value of 1.25 ± 0.19 µM, which was 1.8 times more potent than doxorubicin (IC 50 = 2.31 ± 0.13 µM). In addition, compound 6c exhibited remarkable cytotoxic activity against A549 and MCF-7 cell lines (IC 50 = 1.35 ± 0.12 and 0.49 ± 0.01 µM, respectively), more than two-fold higher than that of doxorubicin. The binding properties of the best active mono- and bis-pyrazolophthalazine (4e and 6c) with HSA and DNA were fully evaluated by various techniques including UV–Vis absorption, circular dichroism (CD), Zeta potential and dynamic light scattering analyses indicating interaction of the compounds with the secondary structure of HSA and significant change of DNA conformation, presumably via a groove binding mechanism. Additionally, molecular docking and site-selective binding studies confirmed the fundamental interaction of compounds 4e and 6c with base pairs of DNA. Compounds 4e and 6c showed promising features to be considered as potential lead structures for further studies in cancer therapy. [ABSTRACT FROM AUTHOR]