Discovery of novel indolyl-1,2,4-triazole hybrids as potent vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors with potential anti-renal cancer activity.

Targeting VEGFR-2 signaling pathway is well-established as an important approach for the treatment of solid tumors, particularly renal cancer. Herein, novel indolyl-1,2,4-triazole hybrids were designed and synthesized as VEGFR-2 kinase inhibitors with potential anti-renal cancer activity. The structures of the newly synthesized compounds were confirmed based on their spectral and elemental analyses. The results of in vitro kinase assay indicated that all target compounds revealed submicromolar inhibition of VEGFR-2 kinase enzyme. Analogs 5c, 5d and 9b emerged as the most active compounds (IC50 = 0.034-0.064 µM), showing VEGFR-2 inhibitory activity much superior to that of sunitinib reference drug (IC50 = 0.075 µM). Moreover, compounds 5a, 8c, 9d, 12c were equipotent to sunitinib against VEGFR-2 kinase. Additionally, the most potent compounds were further examined for their anticancer activity against two human renal cancer cell lines. All screened compounds effectively inhibited the growth of the two tested cell lines with IC50 values spanning from sub-micromolar to low micromolar levels. Compounds 5b, 5d, 11c and 12c were three to five-fold more potent than sunitinib against CAKI-1 cell line. Analogue 8c was superior/comparable to sunitinib against CAKI-1/A498 cell lines. Moreover, compound 9d showed double potency of sunitinib against A498 cell line. Besides, compounds 8c and 12c demonstrated a safety profile much better than that of sunitinib against non-cancer human renal cells. As well, the docked models of title compounds revealed strong interactions with key residues within the active site of VEGFR-2 kinase.

The most recent compilation of reactions of enaminone derivatives with various amine derivatives to generate biologically active compounds.

Heterocyclic derivatives serve as the fundamental components of both natural and synthetic drugs. Enaminones play a crucial role as foundational units in the synthesis of numerous bioactive heterocyclic compounds, including pyrazoles, pyridines, oxazoles, isoxazoles, as well as fused heterocyclic structures like indoles, carbazoles, quinolines, acridines, and phenanthridines. These diverse heterocyclic rings are well-known for their various therapeutic activities, encompassing anticancer, anti-inflammatory, antimicrobial, antidepressant, and antiviral properties. By reacting with nitrogen-based nucleophiles, enaminones can generate bioactive azoles, azines, and their fused systems. This comprehensive review article focuses on the recent advancements in enaminone reactions with (a) nitrogen-based nucleophiles, such as aliphatic amines, derivatives of aniline, heterocyclic amines, hydroxylamine, hydrazine derivatives, guanidine derivatives, urea, and thiourea derivatives, and (b) nitrogen-based electrophiles, such as diazonium salts. These reactions have led to the synthesis of a wide range of bioactive fused heterocyclic compounds from 2010 to the end of 2022.

Novel 2-indolinone thiazole hybrids as sunitinib analogues: Design, synthesis, and potent VEGFR-2 inhibition with potential anti-renal cancer activity.

Novel 2-indolinone thiazole hybrids were designed and synthesized as VEGFR-2 inhibitors based on sunitinib, an FDA-approved anticancer drug. The proposed structures of the prepared 2-indolinone thiazole hybrids were confirmed based on their spectral data and CHN analyses. The target compounds were screened in vitro for their anti-VEGFR-2 activity. All tested compounds exhibited a potent submicromolar inhibition of VEGFR-2 kinase with IC50 values ranging from 0.067 to 0.422 µM, relative to sunitinib reference drug (IC50 = 0.075 ± 0.002 µM). Compounds 5, 15a, 15b, 17, 19c displayed excellent VEGFR-2 inhibitory activity, comparable or nearly equipotent to sunitinib. Compound 13b stood out as the most potent against VEGFR-2 showing IC50 value of 0.067 ± 0.002 µM, lower than that of sunitinib. In addition, the most potent derivatives were assessed for their anticancer activity against two renal cancer cell lines. Compound 13b (IC50 = 3.9 ± 0.13 µM) was more potent than sunitinib (IC50 = 4.93 ± 0.16 µM) against CAKI-1 cell line. Moreover, thiazole 15b displayed excellent anticancer activity against CAKI-1 cell line (IC50 = 3.31 ± 0.11 µM), superior to that of sunitinib (IC50 = 4.93 ± 0.16 µM). Thiazole 15b was also equipotent to sunitinib (IC50 = 1.23 ± 0.04 µM) against A498 cell line. Besides, compound 15b revealed a safety profile much better than that of sunitinib against normal human renal cells. Furthermore, a docking study revealed a proper fitting of the most active compounds into the ATP binding site of VEGFR-2, rationalizing their potent anti-VEGFR-2 activity.

Indomethacin Analogs: Synthesis, Anti-inflammatory and Analgesic Activities of Indoline Derivatives.

BACKGROUND: Microwave assisted reactions offer a considerable advantages over conventional method reactions because the former results in substantial rate enhancement in a wide range of organic reactions. OBJECTIVE: we interested herein to prepare new anti-inflammatory and analgesic agents analogues to Indomethacin in short reaction time by using microwaves irradiation. METHOD: Synthesis of new hydrazonoindolines having thiazole moiety under microwave irradiation were achieved via the reaction of hydrazonoyl chlorides or halogenated active methylene derivatives with thiosemicarbazone derivatives. Also, the utility of the versatile indoline-2,3-dione derivatives in the design of new multifunctional building blocks using condensation with hydrazine derivatives was demonstrated. RESULTS: All products were formed in short reaction time and high yield. The information derived from the spectral data of the formed compounds was confirmed their structures. Also, the analgesic and antiinflammatory activities of the designed derivatives were screened and the results obtained indicated that six derivatives 4g, 9b, 4c, 10b, 4d and 11a revealed the highest anti-inflammatory and analgesic effects. CONCLUSION: we succeeded in this context to design and synthesis of new anti-inflammatory and analgesic agents analogues to Indomethacin in short reaction time and with high yield.