Novel Curcumin Mimics: Design, Synthesis, Biological Properties and Computational Studies of Piperidone‐Piperazine Conjugates

Abstract

alkyl]piperidin-4-ones 7 aÀ k were synthesized through dehydrohalogenation of 1-(2-chloroacyl)piperidin-4-ones 5 aÀ k with N-methylpiperazine (6). High antiproliferation potencies were observed by most of the synthesized agents against both HCT116 (colon) and MCF7 (breast) cancer cell lines relative to the standard references (sunitinib and 5-fluorouracil). The synthesized agents are of dual activity against topoisomerases I and IIα however, with higher efficacy against topoisomerase IIα rather than topoisomerase I. Flow-cytometry cell cycle studies support the observed antiproliferation properties and exhibit the capability of 1-(2-chloroacetyl)-3,5-bis[(E)-4-chlorobenzylidene]piperidin-4-one (5 e) and 3,5-bis[(E)-4-bromobenzylidene]-1-[2-(4-methylpiperazin-1-yl)acetyl]piperidin-4-one (7 g) to arrest the HCT116 cell cycle progression at G1/S and G1 phases, respectively. Noticeable anti-SARS-CoV-2 properties were observed by many synthesized agents. 3,5-Bis[(E)-4-chlorobenzylidene]-1-[3-(4-methylpiperazin-1-yl)propanoyl]piperidin-4-one (7 f) is the most effective anti-SARS-CoV-2 synthesized with high SI. Applicability of the highly effective candidates synthesized as antitumor and anti-SARS-CoV-2 is due to the safety observations against normal (RPE1 and VERO-E6) cells. QSAR models validated internally and externally, support their possibility for optimizing more hits/leads.

Spiroindole-containing compounds bearing phosphonate group of potential Mpro-SARS-CoV-2 inhibitory properties

“…The N -diethyl phosphonate-4-piperidones 3a‒g were synthesized in good to excellent yields (71–87%) through dehydrohalogenation reaction of diethylchlorophosphate 2 with 3,5-bis(ylidene)-4-piperidones 1a‒g in DMF ( N , N -dimethylformamide) in presence of a sufficient amount of TEA (triethylamine) at 0 °C. The single signal integrated to two protons at δ H = 7.67–7.89 evidenced the E -configuration [ [60] , [61] , [62] , [63] ]. Azomethine cycloaddition (obtained through condensation of sarcosine 5 with isatins 4 ) with the appropriate N -diethyl phosphonate-4-piperidones 3a‒g in ethanolic solution under microwave condition (60 Watt, 60 °C) gave the targeted spiroindoles 6a‒l in excellent yields (80–95%) as the only isolable products ( Scheme 1 ).…”

Antineoplastic indole-containing compounds with potential VEGFR inhibitory properties

“…116,117 Many conjugates have been reported to possess diverse potential bio-properties, among which vasodilation is useful for smooth muscle relaxation, 118,119 anti-inflammatory, analgesic, 120–123 antibacterial, 124–126 antimycobacterial, 127 antimalarial, 128 antiviral including anti-SARS-CoV-2, 129–133 HCV “hepatitis C viruses” and chikungunyan, 134 anti-parasitic 135 and antitumor. 136,137…”

Spirooxindole: A Versatile Biologically Active Heterocyclic Scaffold

“…Although advances have been achieved in discovering many chemotherapeutical agents, ideal therapeutics (high efficacy with limited side effects) are unreachable. Progress in research directed toward novel bioactive agents is still encouraged [ 29 , 30 ].…”