<i>S</i>-allylCysteine Ester/Caffeic Acid Amide Hybrids as Promising Antiprotozoal Candidates: Synthesis, Biological Evaluation and Molecular Modeling Studies

Cardona-G, Wilson; Robledo, Sara Maria; Prieto, Laura Juliana; Yépes, Andrés Felipe

doi:10.1590/s2175-97902022e20822

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Brazilian Journal of Pharmaceutical Sciences

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Article • Braz. J. Pharm. Sci. 58 • 2022 • https://doi.org/10.1590/s2175-97902022e20822 copy

S-allylCysteine Ester/Caffeic Acid Amide Hybrids as Promising Antiprotozoal Candidates: Synthesis, Biological Evaluation and Molecular Modeling Studies

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

In order to overcome the challenges of discovering new antiprotozoal drugs, we synthesized a new class of hybrids based on S-allylCysteine Ester/Caffeic Acid Amide and evaluated four of them against Trypanosoma cruzi and Plasmodium falciparum. Hybrid 6 exhibited good activity on T. cruzi with an EC₅₀ value of 5.45 µM, whereas hybrid 3 was active over P. falciparum with an EC₅₀ of 18.08 µM. All hybrids displayed a good selectivity index on P. falciparum. Molecular docking computations indicated that several hybrids have good binding affinities towards the protozoa related enzymes (Cruzipain or Falcipain-2) when compared against current inhibitors. In silico studies showed that conjugates 1-3 and 6 fulfilled optimal ADME characteristics, suggesting them as safe alternatives for oral treatment of protozoal infections.

Keywords:
S-allyl cysteine; Caffeic acid; Hybrid; Chagas disease; Malaria disease; Modelling studies

Compounds	IG^a (%) (X ± SD)	EC₅₀ ^b (T. cruzi, strain Tulahuen) (µg/mL, µM)	Cytotoxicity (U-937 cells) LC₅₀ ^d (µg/mL, µM)	SI^e
1	54.9 ± 2.4	10.8 ± 1.0, 26.65 ± 2.37	4.8 ± 0.1, 11.4 ± 0.2	0.44
2	50.5 ± 3.8^*	5.6 ± 0.8, 12.46 ± 1.78	9.4 ± 1.5, 20.9 ± 3.3	1.68
3	44.2 ± 3.3^**	2.6 ± 0.1, 5.45 ± 0.21	5.1 ± 0.3, 10.7 ± 0.6	1.96
6	40.8 ± 2.3	NR^c	10.3 ± 0.7, 19.8 ± 1.3	ND^f
Benznidazole	60.3 ± 5.7^**	10.5 ± 1.8, 40.3 ± 6.9	179.0 ± 4.2, 687.8 ± 16.1	17.0

Compounds	IG^a (%) (X ± SD)	EC₅₀ ^b (P. falciparum, strain 3D7) (µg/mL, µM)	Cytotoxicity (huGR cells) ^d LC₅₀ (µg/mL, µM)	SI^e
1	60.3 ± 8.8	13.1 ± 1.5, 31.11 ± 3.56	>200	>15.3
2	53.6 ± 7.6	12.2 ± 2.4, 27.16 ± 5.34	>200	>16.4
3	39.6 ± 7.2	NR^c	>200	ND
6	55.9 ± 3.6	9.4 ± 0.5, 18.08 ± 0.96	>200	>21.3
Chloroquine	52.7 ± 8.3^*	0.02 ± 0.01, 0.06 ± 0.03	>200	>10000

Inhibitor	Docking score (kcal/mol)	Bonding Type	Interacting amino acids residues
TCC (PDB: 3IUT)
1	-7.2	H-bond	GLN19, HIS162
		π-π stacked	TRP184
		π-sulfur	MET145
		π-alkyl	ALA141, HIS162
		Hydrophobic	CYS25, GLY23, GLN187, ASP161, CYS22, TRP26, GLY65, ASP140

2	-7.0	H-bond	GLN19, HIS162
		π-π stacked	TRP184
		π-sulfur	MET145
		π-alkyl	ALA141, CYS25
		Hydrophobic	GLY23, ASP161, CYS25, ALA141, GLN187, CYS22, ASN182, THR185


3	-6.8	H-bond	GLN19, HIS162
		π-π stacked	TRP184
		π-sulfur	MET145
		π-alkyl	ALA141
		Hydrophobic	GLY23, ASP161, CYS25, ALA141, GLN187, CYS22, ASN182, THR185

Purine Nitrile	-7.4	H-bond	HIS162, TRP184, GLY20
		π-π stacked	TRP184
		Halogen-F	ASP18
		Hydrophobic	GLN19, CYS22, SER24, ALA141, ASP161, CYS25, MET145, TRP188, THR185, GLN21, SER64, CYS62

TFK	-7.9	H-bond	GLN19, CYS25, GLY66
		π-π stacked	TRP184
		π-sulfur	MET145
		π-σ	SER64
		Hydrophobic	CYS22, TRP188, SER183, THR185, ASN182, TRP144, CYS63, SER64, GLY23, TRP26, ALA27, VAL139, VAL137, VAL164

FP-2 (PDB: 3BPF)
1	-6.6	H-bond	GLN36, HIS174, GLN209
		π-π stacked	TRP206
		π-alkyl	TRP206, ALA157
		Hydrophobic	SER41, CYS39, ASN38, TRP210, ASP154, GLY207, GLY82, ALA175 SER153

2	-7.2	H-bond	GLN36, HIS174, ASN173, CYS39
		π-sulfur	CYS42, LEU172
		π-alkyl	ILE85, LEU84
		Hydrophobic	ALA175, VAL150, TRP206, ASN38, LYS37, GLY40, PHE236, GLN171, VAL176, ASN86, ILE148, TRP43

6	-6.4	H-bond	GLN36, HIS174, TRP206, GLN209
		π-π stacked	TRP206
		π-alkyl	TRP206, VAL152, ALA157
		Hydrophobic	HIS174, GLN36, TRP206, VAL152, ALA157, CYS42, ASN173, SER205, ALA175, ASP35, ASN38, GLY40, CYS39

Epoxysuccinate (E64)	-6.8 (-6.7)^a (-6.9)^b	H-bond	GLN36, TRP206, LYS37
		Salt bridge	ASP35
		π-alkyl	ALA157, VAL152, TRP206
		Hydrophobic	HIS174, CYS42, GLY40, CYS39, SER153, GLY207, SER209, TYR106, SER205, TRP210, ASP154, SER153, SER108.

Chloroquine	-6.3 (-5.8)^a (-6.5)^c	π-π stacked	TRP206
		π-alkyl	ALA157, TRP210
		Hydrophobic	GLN36, CYS42, HIS174, GLN209, ASN173, GLY40, ASN38, CYS39, VAL152, SER205, PHE158, LYS37

Entry	M.W ^a	PSA ^b	n-Rot Bond (0-10)	n-ON^c	n-OHNH^d	Log P_o/w ^e	Log K_HSA ^f	App. Caco-2 ^g	App. MDCK (nm/s) ^h	% HIA ⁱ	Lipinski Rule of five (≤1)
Caffeic acid	180.160	96.196	2.0	4.0	3.0	0.538	-0.803	21	10	75.8	0
Allylcysteine	161.218	72.680	5.0	3.0	3.0	-1.533	-0.891	23	17	83.9	0
1	421.464	129.800	11.0	8.0	1.0	3.025	-0.236	530	321	64.2	1
2	449.518	123.439	13.0	8.0	1.0	3.960	-0.029	1011	754	66.4	1
3	477.571	129.308	15.0	8.0	1.0	4.686	0.284	621	389	64.4	1
6	519.652	129.377	18.0	8.0	1.0	5.597	0.527	834	513	86.0	1

hybrid	T_1/2 [hr]^a,b
hybrid	Human	Rat	Mouse
1	0.786	7.586	0.997
2	0.690	3.93	0.972
3	0.665	4.808	0.883
6	0.663	3.824	0.991

Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br

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[1] *Correspondence: A. F. Yepes. Química de Plantas Colombianas. Faculty of Exact and Natural Sciences. Institute of Chemistry. Universidad de Antioquia, 57 (4) 219 5650, Medellín, Colombia. E-mail: andresf.yepes@ udea.edu.co.