Quinazoline-based VEGFR-2 inhibitors as potential anti-angiogenic agents: A contemporary perspective of SAR and molecular docking studies

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

Efficient synthesis, biological evaluation, and docking study of isatin based derivatives as caspase inhibitors

In this paper, a new series of isatin-sulphonamide based derivatives were designed, synthesised and evaluated as caspase inhibitors. The compounds containing 1-(pyrrolidinyl)sulphonyl and 2-(phenoxymethyl)pyrrolidin-1-yl)sulphonyl substitution at C5 position of isatin core exhibited better results compared to unsubstituted derivatives. According to the results of caspase inhibitory activity, compound 20d showed moderate inhibitory activity against caspase-3 and −7 in vitro compared to Ac-DEVD-CHO (IC50 = 0.016 ± 0.002 μM). Among the studied compounds, some active inhibitors with IC50s in the range of 2.33–116.91 μM were identified. The activity of compound 20d was rationalised by the molecular modelling studies exhibiting the additional van der Waals interaction of N-phenylacetamide substitution along with efficacious T-shaped π-π and pi-cation interactions. The introduction of compound 20d with good caspase inhibitory activity will help researchers to find more potent agents

An efficient, four-component reaction for the synthesis of novel carbamodithioates

<p>A series of substituted phenylcarbamoyl methyl benzylcarbamodithioates have been synthesized using the multicomponent condition. The reaction proceeded under mild practical condition and afforded the desired products in good yields.</p

Efficient three-step synthesis of benzo[<i>e</i>]imidazo[1,2-<i>c</i>][1,2,3]triazines

<p>A novel three-step sequence toward benzo[<i>e</i>]imidazo[1,2-<i>c</i>][1,2,3]triazine derivatives is investigated. This pathway started from commercially available starting materials afforded <b>5a–h</b> in good to excellent yields. In this method, we took the advantage of diazonium chemistry, which was followed by intramolecular N-N bond formation in the construction of N-rich cycles.</p

Straightforward Approach Toward Dihydrothiazoles via Intramolecular Bromocyclization

<div><p></p><p>An intramolecular bromonium ion–assisted cyclization with sulfur as an internal nucleophile is described. Starting from benzoyl chlorides, this method provides an easy procedure for the synthesis of dihydrothiazole derivatives in moderate to good yields.</p></div

Quinoline-based imidazole-fused heterocycles as new inhibitors of 15-lipoxygenase

<p>A series of 2-chloro-quinoline-based imidazopyridines <b>6a–l</b> and imidazothiazoles <b>6m–o</b> bearing a bulky alkylamine side chain were synthesized as soybean 15-LOX inhibitors. The target compounds <b>6a–o</b> were prepared <i>via</i> one-pot reaction of 2-chloroquinoline-3-carbaldehyde (<b>3</b>), heteroaromatic amidine <b>4</b>, and alkyl isocyanides <b>5</b>, in the presence of NH₄Cl. All compounds showed significant anti-15-LOX activity (IC₅₀ values ≤40 μM). Among the title compounds, the imidazo[2,1-<i>b</i>]thiazole derivative <b>6n</b> bearing a <i>tert</i>-butylamine moiety showed the highest activity against soybean 15-LOX enzyme.</p

Design, synthesis, molecular docking, and in vitro α-glucosidase inhibitory activities of novel 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines against yeast and rat α-glucosidase

Abstract 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