Phthalimides Represent a Promising Scaffold for Multi‐Targeted Anticancer Agents

Abstract

From the last two decades, phthalimide analogues received prime interest from scientists due to its potent inhibitory action on different cancer-causing receptors. A variety of anticancer drugs are coming into the market but challenges of drug resistance, toxicities, and failure in therapy still remain. Cancer is a group of complex disorders it involves multiple receptors. So there is a need of targeting multiple receptors to get desired potent anticancer drugs with minimum harmful effects. Phthalimide scaffolds fit into these criteria as it is extensively reported for the inhibition of different cancer receptors such as VEGFR, HDAC, EGFR, TNF-α, etc. The multi-targeted mechanism of phthalimide derivatives plays a major role in anticancer therapy. Due to this advantage, there is the hope of developing some novel effective multi-targeted anticancer agents. Consider structural features and pharmacological advancement of phthalimide analogues may fulfill the current need of cancer patients. In this review, we covered history, chemistry, SAR, anticancer mechanisms, and the current status of phthalimide derivatives reported till 2022. The article specifically focused on different cancer-causing receptors inhibited by phthalimide derivatives and their mechanism of action in brief. Finally, we provided the future scope and role of phthalimide derivatives in multi-targeted anticancer drug discovery.

Electrooxidative Hofmann Rearrangement of Phthalimides to Access Anthranilate Derivatives

“…Phthalimide and its analogues are widely used in organic synthesis as versatile building blocks, as well as in the field of pharmaceutical chemistry due to their rich biological activities . Recently, we realized the electrosynthesis of N -acylsulfenamides by the direct thiolation of amides (phthalimides, isatins, and aliphatic amides) with mercaptans through the formation of N–S bonds .…”

“…Phthalimide and its analogues are widely used in organic synthesis as versatile building blocks, 13 as well as in the field of pharmaceutical chemistry due to their rich biological activities. 14 Recently, we realized the electrosynthesis of N -acylsulfenamides by the direct thiolation of amides (phthalimides, isatins, and aliphatic amides) with mercaptans through the formation of N–S bonds. 15 Inspired by the acquired advances in electrochemical Hofmann reactions and our continuous interest in heterocyclic transformation 16 and organic electrosynthesis, 17 we herein report a Hofmann rearrangement scheme for the direct conversion of phthalimides to the corresponding anthranilate derivatives via alcoholysis under electrooxidative conditions in the absence of transition-metal catalysts and excessive extra oxidants ( Scheme 1 d).…”

Synthesis, characterization, anti‐proliferative evaluation, and molecular docking study of some new N‐(1, 3‐dioxoisoindolin‐4‐yl)acetamide derivatives

“…Among these molecules, phthalimide core moiety gets scientific community attention due to biological active scaffolds [14][15][16]. Moreover, the phthalimide scaffolds have extended therapeutic efficacy toward various diseases, such as anticancer [17,18], anti-inflammatory [19,20], anxiolytic [21], anthelmintic [22], anti-HIV-1 [23]. In addition to that phthalimides (isoindole-1, 3-diones) also act as inhibitors of TNF-alpha (tumor necrosis factor) and played immune response against various diseases [24].…”

Rhodium-catalysed additive-free carbonylation of benzamides with diethyl dicarbonate as a carbonyl source

“…[13][14][15] Intramolecular carbonylation of benzamides is intriguing as it enables the direct synthesis of pharmaceutically relevant phthalimide motifs from a simple starting material (Scheme 1A). [16][17][18] Although carbon monoxide (CO) has been commonly employed in phthalimide syntheses as an economical C1 carbonyl source, its use is constrained by toxicity and flammability. Furthermore, these carbonylations with CO often necessitate oxidative reaction conditions, requiring expensive and toxic chemical oxidants like silver salts (Scheme 1B).…”