Monoketone Curcuminoids: An Updated Review of Their Synthesis and Biological Activities

Citation:Vieira, T.M.; Tanajura, L.S.;

Heleno, V.C.G.; Magalhães, L.G.;

Crotti, A.E.M. Monoketone Curcuminoids: An Updated Review of Their Synthesis and Biological Activities.Future Pharmacol.2024,4, 54–76. https://doi.org/10.3390/

futurepharmacol4010006 Academic Editor: Shreesh Kumar Ojha

Received: 3 December 2023 Revised: 28 December 2023 Accepted: 9 January 2024 Published: 17 January 2024

Copyright: © 2024 by the authors.

Licensee MDPI, Basel, Switzerland.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://

creativecommons.org/licenses/by/

4.0/).

Review

Monoketone Curcuminoids: An Updated Review of Their Synthesis and Biological Activities

Tatiana M. Vieira¹, Lívia S. Tanajura¹ , Vladimir C. G. Heleno², Lizandra G. Magalhães² and Antônio E. M. Crotti^2,*

1 Department of Chemistry, Faculty of Philosophy, Sciences and Letters, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil; tati.manzini@gmail.com (T.M.V.); liviastenico@gmail.com (L.S.T.)

2 Center for Research on Natural Products, University of Franca, Franca 14404-600, SP, Brazil;

vladimir.heleno@unifran.edu.br (V.C.G.H.); lizandra.magalhaes@unifran.edu.br (L.G.M.)

* Correspondence: millercrotti@ffclrp.usp.br; Tel.: +55-16-35153747

Abstract:Curcumin (or diferuloylmethane), a component ofCurcuma longaL. rhizomes, displays various biological and pharmacological activities. However, it is poorly bioavailable and unstable in physiological pH. In this review, we cover papers published between 2019 and 2023 on the synthesis and biological activities of more stable and effective curcumin analogs known as monoketone curcum- inoids (MKCs) or “monocarbonyl curcuminoids.” Recent advances in Claisen–Schmidt condensation, the standard procedure to synthesize MKCs, including the use of ionic liquids, are addressed. MKCs’

antimicrobial, anticancer, antioxidant, and antiparasitic actions, as well as other less common MKC bi- ological and pharmacological activities, have been shown to be similar or higher than curcumin. The promising biological and pharmacological activities, combined with the attractive synthetic aspects (e.g., good yields and an easiness of product isolation) to obtain MKCs, make this class of compounds an interesting prospect for further antimicrobial, anticancer, and antiparasitic drug discovery.

Keywords:Claisen–Schmidt condensation; deketene curcuminoid; diarylpentanoids; monocarbonyl curcuminoids; monoketone curcuminoids

1. Introduction

Curcumin (or 1,7-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) (I, Figure1), also known as diferuloylmethane, is one of the main hydrophobic phenolic compounds found in Curcuma longa L. (Zingiberaceae) rhizomes [1]. Curcumin and its analogs, demethoxycurcumin (II) and bisdemethoxycurcumin (III), also present inC. longarhi- zomes, are commonly referred to as curcuminoids [2].

 

   

 

Future Pharmacol. 2024, 4, Firstpage–Lastpage. https://doi.org/10.3390/xxxxx  www.mdpi.com/journal/futurepharmacol 

Review 

Monoketone Curcuminoids: An Updated Review of Their    Synthesis and Biological  Activities 

Tatiana M. Vieira ¹, Lívia S. Tanajura ¹, Vladimir C. G. Heleno ², Lizandra G. Magalhães ² and Antônio E. M. Crotti ^2,* 

1  Department of Chemistry, Faculty of Philosophy, Sciences and Letters, University of São Paulo,    Ribeirão Preto 14040-901, SP, Brazil; tati.manzini@gmail.com (T.M.V.), liviastenico@gmail.com (L.S.T.) 

2  Center for Research on Natural Products, University of Franca, Franca 14404-600, SP, Brazil;   

vladimir.heleno@unifran.edu.br (V.C.G.H.); lizandra.magalhaes@unifran.edu.br (L.G.M.) 

*  Correspondence: millercrotti@ffclrp.usp.br; Tel.: +55-16-35153747 

Abstract: Curcumin (or diferuloylmethane), a component of Curcuma longa L. rhizomes, displays  various biological and pharmacological activities. However, it is poorly bioavailable and unstable  in physiological pH. In this review, we cover papers published between 2019 and 2023 on the syn- thesis and biological activities of more stable and effective curcumin analogs known as monoketone  curcuminoids (MKCs) or “monocarbonyl curcuminoids.” Recent advances in Claisen–Schmidt con- densation, the standard procedure to synthesize MKCs, including the use of ionic liquids, are ad- dressed. MKCs’ antimicrobial, anticancer, antioxidant, and antiparasitic actions, as well as other less  common MKC biological and pharmacological activities, have been shown to be similar or higher  than curcumin. The promising biological and pharmacological activities, combined with the attrac- tive synthetic aspects (e.g., good yields and an easiness of product isolation) to obtain MKCs, make  this class of compounds an interesting prospect for further antimicrobial, anticancer, and antipara- sitic drug discovery. 

Keywords: Claisen–Schmidt condensation; deketene curcuminoid; diarylpentanoids; monocar- bonyl curcuminoids; monoketone curcuminoids 

 

1. Introduction 

Curcumin (or 1,7-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) (I, Figure 1),  also known as diferuloylmethane, is one of the main hydrophobic phenolic compounds  found in Curcuma longa L. (Zingiberaceae) rhizomes [1]. Curcumin and its analogs, de- methoxycurcumin (II) and bisdemethoxycurcumin (III), also present in C. longa rhizomes,  are commonly referred to as curcuminoids [2]. 

 

Figure 1. Chemical structures of curcumin (I), demethoxycurcumin (II), and bisdemethoxycurcu- min (III). 

Besides being used as a supplement, seasoning, food preservative, flavoring, and col- oring in the food industry [3], curcumin has various biological and pharmacological ac- tivities, including antioxidant [4], anti-inflammatory [5], antimicrobial [6], anticancer [7],  and antiparasitic [8] actions. However, limitations have prevented it from being approved  as a therapeutic agent. For example, curcumin is poorly bioavailable, because it is barely 

Citation: Vieira, T.M.; Tanajura, L.S.; 

Heleno, V.C.G.; Magalhães, L.G.; 

Crotti, A.E.M. Monoketone    Curcuminoids: An Updated Review  of Their Synthesis and Biological    Activities. Future Pharmacol. 2024, 4,  x. https://doi.org/10.3390/xxxxx 

Academic Editor: Shreesh Kumar  Ojha 

Received: 3 December 2023  Revised: 28 December 2023  Accepted: 9 January 2024  Published: 17 January 2024 

 

Copyright: © 2024 by the authors. 

Submitted for possible open access  publication  under  the  terms  and  conditions of the Creative Commons  Attribution  (CC  BY)  license  (https://creativecommons.org/license s/by/4.0/). 

Figure 1.Chemical structures of curcumin (I), demethoxycurcumin (II), and bisdemethoxycurcumin (III).

Besides being used as a supplement, seasoning, food preservative, flavoring, and coloring in the food industry [3], curcumin has various biological and pharmacological activities, including antioxidant [4], anti-inflammatory [5], antimicrobial [6], anticancer [7], and antiparasitic [8] actions. However, limitations have prevented it from being approved as a therapeutic agent. For example, curcumin is poorly bioavailable, because it is barely

Future Pharmacol.2024,4, 54–76. https://doi.org/10.3390/futurepharmacol4010006 https://www.mdpi.com/journal/futurepharmacol

Future Pharmacol.2024,4 55

absorbed and rapidly metabolized [9]. Moreover, it has low chemical stability under physi- ological conditions, because itsβ-diketone moiety is prone to hydrolysis [10]. Furthermore, it undergoes rapid light-induced decomposition [11]

The diverse biological activities of curcumin and its low bioavailability and stability have motivated the synthesis of curcumin analogs bearing a modifiedβ-diketone portion or new substituents in the aromatic moiety [10]. Replacing theβ-diketone portion with a monocarbonyl portion increases the chemical stability of the resulting monoketone cur- cuminoid (MKC) under physiological conditions [12] and provides the compounds with interesting biological actions [13]. However, MKCs (IV, Figure2) have a controversial and confusing nomenclature. In the literature, the terms “diphenylpentanoids,” “diben- zylidene ketones,” “1,5-diaryl-penta-1,4-diene-3-ones,” “diarylpentanoids,” “monoketone curcuminoids,” “C5-curcuminoids,” “monocarbonyl curcuminoids,” “deketene curcumin,”

and “monocarbonyl curcumin” are used to refer to them. Nevertheless, the general term

“curcuminoids,” which includes the dicarbonyl compounds, has been used most often.

The lack of a uniform nomenclature for MKCs not only makes searching for them in the literature challenging, but also causes their importance to be underestimated.

Future Pharmacol. 2024, 4,  2 

 

 

absorbed and rapidly metabolized  [9]. Moreover, it has  low chemical stability under phys- iological  conditions,  because its β-diketone  moiety  is  prone to hydrolysis  [10].  Further- more, it undergoes rapid light-induced decomposition [11] 

The diverse biological activities of curcumin and its low bioavailability and stability  have motivated the synthesis of curcumin analogs bearing a modified β-diketone portion  or new substituents in the aromatic moiety [10]. Replacing the β-diketone portion with a  monocarbonyl portion increases the chemical stability of the resulting monoketone curcu- minoid (MKC) under physiological conditions [12] and provides the compounds with in- teresting biological actions [13]. However, MKCs (IV, Figure 2) have a controversial and  confusing  nomenclature.  In  the literature,  the  terms  “diphenylpentanoids,” “dibenzyli- dene  ketones,”  “1,5-diaryl-penta-1,4-diene-3-ones,”  “diarylpentanoids,”  “monoketone  curcuminoids,”  “C5-curcuminoids,”  “monocarbonyl  curcuminoids,”  “deketene  curcu- min,” and “monocarbonyl curcumin” are used to refer to them. Nevertheless, the general  term “curcuminoids,” which includes the dicarbonyl compounds, has been used most of- ten. The lack of a uniform nomenclature for MKCs not only makes searching for them in  the literature challenging, but also causes their importance to be underestimated. 

According to  Moreira  and co-workers, symmetric (Ar = Ar’)  and asymmetric (Ar ≠  Ar’) MKCs are classified on the basis of the carbon atoms of the C5 unit, and the classifi- cation depends on whether these carbon atoms are part of an acyclic skeleton or belong to  a cyclic fraction. When MKCs bear a cyclic C5 unit, this unit can be part of a cyclopenta- none  (V),  cyclohexanone  (VI),  piperidin-4-one (VII), tetrahydro-4H-pyran-4-one  (VIII),  or a tetrahydro-4H-thiopiran-4-one (IX) (Figure 2) [14]. 

  Figure 2. Structures of MKCs displaying an acyclic (IV) and a cyclic C5 bridge (V–IX) [14]. 

Although extensive reviews on MKCs’ biological activities have been published over  the  last  decade [12,15,16],  a  review spanning  a  more  recent  period would  be welcome. 

Here, we provide an overview of the recent literature (2019–2023) on the biological activ- ities of MKCs and address some aspects of their synthesis and biological activities (e.g.,  their insecticidal activity) that have not been discussed yet. The structures of MKCs 1–48  (symmetric acetone-derived MKCs), 49–73  (asymmetric acetone-derived  MKCs), 74–103  (cyclopentanone-derived MKCs), 104–151 (cyclohexanone-derived MKCs),  152–169 (4-hy- droxy-cyclohexanone-derived  MKCs),  170–227  (piperidin-4-one-derived  MKCs),  and  228–254 (tetrahydro-4H-pyran-4-one-derived MKCs) addressed in this review article are  shown in Figures 3–9, respectively. 

Figure 2.Structures of MKCs displaying an acyclic (IV) and a cyclic C5 bridge (V–IX) [14].

According to Moreira and co-workers, symmetric (Ar = Ar’) and asymmetric (Ar̸=Ar’) MKCs are classified on the basis of the carbon atoms of the C5 unit, and the classification depends on whether these carbon atoms are part of an acyclic skeleton or belong to a cyclic fraction. When MKCs bear a cyclic C5 unit, this unit can be part of a cyclopentanone (V), cyclohexanone (VI), piperidin-4-one (VII), tetrahydro-4H-pyran-4-one (VIII), or a tetrahydro-4H-thiopiran-4-one (IX) (Figure2) [14].

Although extensive reviews on MKCs’ biological activities have been published over the last decade [12,15,16], a review spanning a more recent period would be welcome.

Here, we provide an overview of the recent literature (2019–2023) on the biological activ- ities of MKCs and address some aspects of their synthesis and biological activities (e.g., their insecticidal activity) that have not been discussed yet. The structures of MKCs 1–48 (symmetric acetone-derived MKCs), 49–73 (asymmetric acetone-derived MKCs), 74–103(cyclopentanone-derived MKCs),104–151(cyclohexanone-derived MKCs),152–169 (4-hydroxy-cyclohexanone-derived MKCs),170–227(piperidin-4-one-derived MKCs), and 228–254(tetrahydro-4H-pyran-4-one-derived MKCs) addressed in this review article are shown in Figures3–9respectively.

Future Pharmacol.Future Pharmacol. 2024, 4, 2024,4 3  56  

 

  Figure 3. Chemical structures of symmetric acetone-derived MKCs 1–48. 

  Figure 4. Chemical structures of asymmetric acetone-derived MKCs 49–73. 

O

OCH3 H3CO

O 39-45 O

O O

39: R=4-F 40: R=2-Cl 41: R=2-F 42: R=3-CF₃

43: R=3-NO₂ 44: R=4-NO₂ 45: R=4-CH₃

R R

O

Cl Cl

38

O O

Cl Cl

O

N

N Cl Cl

R R

46: R=7-OMe 47: R=7-Me 48: R=7-OEt O

R1 R₂ R₃

R1 R₂

R₃ R₄

R₅ R₅ R₄ 1: R₁=R₂=R₃=R₅=H

2:R₁=OH, R₂=R₃=R₄=R₅=H 3: R₃=OH, R₁=R₂=R₄=R₅=H 4: R₂=R3=OH, R1=R4=R5=H 5:R₁=OH, R₃=OCH₃, R₂=R₄=H 6: R₂=R3=R4=OH, R1=R5=H 7: R₁=OCH_3,R₂=R₃=R₄=R₅=H 8:R1=R2=OCH3,R3=R4=R5=H 9: R₂=OCH₃, R₁=R₃=R₄=R₅=H 10: R₂=OCH3,R3=OH, R1=R4=R5=H 11: R₃=OCH₃, R₁=R₂=R₄=R₅=H

23: R₁=Cl, R₂=R₃=R₄=R₅=H 24: R₃=Cl, R₁=R₂=R₄=R₅=H 25: R₁=R₃=Cl, R₂=R₄=R₅=H 26: R₁=Br, R2=R3=R4=R5=H 27: R₂=Br, R₁=R₃=R₄=R₅=H 28: R₃=Br, R1=R2=R4=R5=H 29: R₃=CN, R₁=R₂=R₄=R₅=H 30: R₁=NO2, R2=R3=R4=R5=H 31: R₂=NO₂, R₁=R₃=R₄=R₅=H 32: R₃=NO2, R1=R2=R4=R5=H

O R

O

R

36:R=OCH₃ O 37: R=OCH₂CH₃

O 33

O

X X

34: X=O 35: X=S 12: R₂=R₃=OCH₃, R₁=R₄=R₅=H

13: R₁=R₂=R₃=OCH_3,R₄=R₅=H 14: R₁=R₃=R₅=OCH_3,R₂=R₄=H 15:R2=R4=OMe, R1=R3=R5=H 16:R₂=R₃=R₄=OCH_3,R₁=R₅=H 17: R₁=OCH2CH3, R2=R3=R4=R5=H 18: R₁=CH₃, R₂=R₃=R₄=R₅=H 19: R₂=CH3,R1=R3=R4=R5=H 20: R₃=CH_3,R₁=R₂=R₄=R₅=H 21: R₁=CF3, R2=R3=H 22: R₃=F, R₁=R₂=R₄=R₅=H

1-32

Figure 3.Chemical structures of symmetric acetone-derived MKCs1–48.

Future Pharmacol. 2024, 4,  3 

 

 

  Figure 3. Chemical structures of symmetric acetone-derived MKCs 1–48. 

  Figure 4. Chemical structures of asymmetric acetone-derived MKCs 49–73. 

O

OCH₃ H₃CO

O 39-45 O

O O

39: R=4-F 40: R=2-Cl 41: R=2-F 42: R=3-CF₃

43: R=3-NO₂ 44: R=4-NO₂ 45: R=4-CH₃

R R

O

Cl Cl

38

O O

Cl Cl

O

N

N Cl Cl

R R

46: R=7-OMe 47: R=7-Me 48: R=7-OEt O

R₁ R₂ R₃

R₁ R₂

R₃ R₄

R₅ R₅ R₄ 1: R₁=R₂=R₃=R₅=H

2:R₁=OH, R₂=R₃=R₄=R₅=H 3: R₃=OH, R₁=R₂=R₄=R₅=H 4: R₂=R₃=OH, R₁=R₄=R₅=H 5:R₁=OH, R₃=OCH₃, R₂=R₄=H 6: R₂=R₃=R₄=OH, R₁=R₅=H 7: R₁=OCH_3,R₂=R₃=R₄=R₅=H 8:R₁=R₂=OCH_3,R₃=R₄=R₅=H 9: R₂=OCH₃, R₁=R₃=R₄=R₅=H 10: R₂=OCH_3,R₃=OH, R₁=R₄=R₅=H 11: R₃=OCH₃, R₁=R₂=R₄=R₅=H

23: R₁=Cl, R₂=R₃=R₄=R₅=H 24: R₃=Cl, R₁=R₂=R₄=R₅=H 25: R₁=R₃=Cl, R₂=R₄=R₅=H 26: R₁=Br, R₂=R₃=R₄=R₅=H 27: R₂=Br, R₁=R₃=R₄=R₅=H 28: R₃=Br, R₁=R₂=R₄=R₅=H 29: R₃=CN, R₁=R₂=R₄=R₅=H 30: R₁=NO₂, R₂=R₃=R₄=R₅=H 31: R₂=NO₂, R₁=R₃=R₄=R₅=H 32: R₃=NO₂, R₁=R₂=R₄=R₅=H

O R

O

R

36:R=OCH₃ O 37: R=OCH₂CH₃

O

33

O

X X

34: X=O 35: X=S 12: R₂=R₃=OCH₃, R₁=R₄=R₅=H

13: R₁=R₂=R₃=OCH_3,R₄=R₅=H 14: R₁=R₃=R₅=OCH_3,R₂=R₄=H 15:R₂=R₄=OMe, R₁=R₃=R₅=H 16:R₂=R₃=R₄=OCH_3,R₁=R₅=H 17: R₁=OCH₂CH₃, R₂=R₃=R₄=R₅=H 18: R₁=CH₃, R₂=R₃=R₄=R₅=H 19: R₂=CH_3,R₁=R₃=R₄=R₅=H 20: R₃=CH_3,R₁=R₂=R₄=R₅=H 21: R₁=CF₃, R₂=R₃=H 22: R₃=F, R₁=R₂=R₄=R₅=H

1-32

Figure 4.Chemical structures of asymmetric acetone-derived MKCs49–73.

Future Pharmacol.Future Pharmacol. 2024, 4, 2024,4 4 57  

 

  Figure 5. Chemical structures of cyclopentanone-derived MKCs 74–103. 

  Figure 6. Chemical structures of cyclohexanone-derived MKCs 104–151. 

O EtO

O

OEt O 120

O

Cl Cl

147

O O

Cl Cl

O

N

N Cl Cl

R R

113: R=H 114: R=7-OMe 115: R=7-Me 116: R=7-OEt

117: R=6-Cl 118: R=6-OMe 119: R=6-Me R₁ O

R₂ R₃

R₁ R₂ R₃ 104: R₁=R₂=R₃=R₄=H

105: R₃=CH₃, R₁=R₂=R₄=H 106: R₃=OCH_3,R₁=R₂=R₄=H 107: R₂=OCH_3,R₃=OH, R₁=R₄=H 108:R₂=R₃=R₄=OCH_3,R₁=H 109: R₃=Cl, R₁=R₂=R₄=H 110: R₁=Cl, R₂=R₃=R₄=H 111: R₃=F, R₁=R₂=R₄=H 112: R₂=R₄=OCH_3,R₁=R₃=H

R₄ R₄

O

R₂

R₄ R₅

121: R₅=OCH_3,R₁=R₂=R₃=R₄=H 122: R₄=OH, R₁=R₂=R₃=R₅=H 123: R₅=OH, R₁=R₂=R₃=R₄=H 124: R₄=R₅=OH, R₁=R₂=R₃=H 125: R₄=OCH_3,R₅=OH, R₁=R₂=R₃=H 126: R₅=N(CH₃)₂, R₁=R₂=R₃=R₄=H 127: R₅=CH_3,R₁=R₂=R₃=R₄=H 128: R₅=Cl, R₁=R₂=R₃=R₄=H 129: R₄=R₅=Cl, R₁=R₂=R₃=H, 130: R₅=Br, R₁=R₂=R₃=R₄=H 131: R₅=CF_3,R₁=R₂=R₃=R₄=H 132: R₄=NO_2,R₁=R₂=R₃=R₅=H 133: R₂=OCH₃, R₃=R₄=R₅=OH, R₁=H

134: R₁=Br, R₅=OH, R₂=R₃=R₄=H 135: R₁=Br, R₄=OH, R₂=R₃=R₅=H 136: R₁=R₅=OH, R₂=R₃=R₄=H 137: R₁=R₄=OH, R₂=R₃=R₅=H 138: R₂=R₅=OH, R₁=R₃=R₄=H 139: R₂=Br, R₅=OH, R₁=R₃=R₄=H 140: R₂=Br, R₄=OH, R₁=R₃=R₅=H 141: R₁=OCH_3,R₅=OH, R₂=R₃=R₄=H 142: R₁=OCH_3,R₄=OH, R₂=R₃=R₅=H 143: R₂=OCH_3,R₄=OH, R₁=R₃=R₅=H 144: R₁=R₂=OCH_3,R₄=OH, R₃=R₅=H 146: R₁=R₂=R₃=OCH_3,R₅=OH, R₄=H R₁

O

X X

148: X=O 146: X=S R₃

O

R₃ R₃

CH₃ 150: R=H 151: R=Cl 121-146

Figure 5.Chemical structures of cyclopentanone-derived MKCs74–103.

Future Pharmacol. 2024, 4,  4 

 

 

  Figure 5. Chemical structures of cyclopentanone-derived MKCs 74–103. 

  Figure 6. Chemical structures of cyclohexanone-derived MKCs 104–151. 

O EtO

O

OEt O 120

O

Cl Cl

147

O O

Cl Cl

O

N

N Cl Cl

R R

113: R=H 114: R=7-OMe 115: R=7-Me 116: R=7-OEt

117: R=6-Cl 118: R=6-OMe 119: R=6-Me O

R₁ R2

R3

R₁ R2

R3

104: R₁=R₂=R₃=R₄=H 105: R3=CH3, R1=R2=R4=H 106: R3=OCH3,R1=R2=R4=H 107: R2=OCH3,R3=OH, R1=R4=H 108:R2=R3=R4=OCH3,R1=H 109: R₃=Cl, R1=R2=R4=H 110: R₁=Cl, R2=R3=R4=H 111: R₃=F, R1=R2=R4=H 112: R₂=R4=OCH3,R1=R3=H

R4 R4

O

R2

R4

R5

121: R₅=OCH_3,R₁=R₂=R₃=R₄=H 122: R₄=OH, R1=R2=R3=R5=H 123: R5=OH, R1=R2=R3=R4=H 124: R₄=R₅=OH, R₁=R₂=R₃=H 125: R₄=OCH3,R5=OH, R1=R2=R3=H 126: R5=N(CH3)2, R1=R2=R3=R4=H 127: R₅=CH_3,R₁=R₂=R₃=R₄=H 128: R₅=Cl, R1=R2=R3=R4=H 129: R4=R5=Cl, R1=R2=R3=H, 130: R₅=Br, R₁=R₂=R₃=R₄=H 131: R₅=CF3,R1=R2=R3=R4=H 132: R4=NO2,R1=R2=R3=R5=H 133: R₂=OCH₃, R₃=R₄=R₅=OH, R₁=H

134: R₁=Br, R₅=OH, R₂=R₃=R₄=H 135: R₁=Br, R4=OH, R2=R3=R5=H 136: R₁=R₅=OH, R₂=R₃=R₄=H 137: R₁=R4=OH, R2=R3=R5=H 138: R₂=R₅=OH, R₁=R₃=R₄=H 139: R₂=Br, R5=OH, R1=R3=R4=H 140: R2=Br, R4=OH, R1=R3=R5=H 141: R₁=OCH_3,R₅=OH, R₂=R₃=R₄=H 142: R1=OCH3,R4=OH, R2=R3=R5=H 143: R₂=OCH_3,R₄=OH, R₁=R₃=R₅=H 144: R₁=R2=OCH3,R4=OH, R3=R5=H 146: R₁=R₂=R₃=OCH_3,R₅=OH, R₄=H R1

O

X X

148: X=O 146: X=S R₃

O

R3 R3

CH₃ 150: R=H 151: R=Cl 121-146

Figure 6.Chemical structures of cyclohexanone-derived MKCs104–151.

Future Pharmacol.Future Pharmacol. 2024, 4, 2024,4 5  58  

 

  Figure 7. Chemical structures of 4-hydroxy-cyclohexanone-derived MKCs 152–169. 

  Figure 8. Chemical structures of 4-piperidone-derived MKCs 170–227. 

166: Ar = 167: Ar =

N N

Ar O

Ar

OH 166-167

O

O O

O O

168O

O

O O

Cl 169 O

R2

R2

R3 R3

R₁ R₁

OH 152-165

152: R₁=R2=R3=H 153: R₃=Cl, R₁=R₂=H 154: R₁=R₃=Cl, R₂=H 155: R₂=Cl, R₁=R₃=H 156: R₁=Cl, R₂=R₃=H 157: R3=NO2, R1=R2=H 158: R1=NO2, R2=R3=H

159: R₂=NO2, R1=R3=H 160: R₃=N(CH₃)_2,R₁=R₂=H 161: R₃=OCH₃, R₁=R₂=H 162: R₂=R₃=OCH_3,R₁=H 163: R₂=OCH_3,R₁=R₃=H 165: R3=CH3,R1=R2=H

Figure 7.Chemical structures of 4-hydroxy-cyclohexanone-derived MKCs152–169.

Future Pharmacol. 2024, 4,  5 

 

 

  Figure 7. Chemical structures of 4-hydroxy-cyclohexanone-derived MKCs 152–169. 

  Figure 8. Chemical structures of 4-piperidone-derived MKCs 170–227. 

166: Ar = 167: Ar =

N N

Ar O

Ar

166-167OH

O

O O

O O

168O

O

O O

Cl 169 O

R2

R2

R3 R3

R1 R1

OH 152-165

152: R₁=R₂=R₃=H 153: R₃=Cl, R₁=R₂=H 154: R₁=R3=Cl, R2=H 155: R₂=Cl, R1=R3=H 156: R₁=Cl, R₂=R₃=H 157: R₃=NO₂, R₁=R₂=H 158: R₁=NO2, R2=R3=H

159: R₂=NO₂, R₁=R₃=H 160: R₃=N(CH₃)_2,R₁=R₂=H 161: R₃=OCH3, R1=R2=H 162: R₂=R3=OCH3,R1=H 163: R₂=OCH_3,R₁=R₃=H 165: R₃=CH_3,R₁=R₂=H

Figure 8.Chemical structures of 4-piperidone-derived MKCs170–227.