In vitro bioevaluation and docking study of dihydrosphingosine and ethambutol analogues against sensitive and multi-drug resistant Mycobacterium tuberculosis

Eur J Med Chem. 2023 Oct 5:258:115579. doi: 10.1016/j.ejmech.2023.115579.

Leonardo Aquino Linhares ¹, Aline Dos Santos Peixoto ², Luanna de Angelis Correia de Sousa ², João Paulo Lucena Laet ², Aline Caroline da Silva Santos ³, Valeria Rêgo Alves Pereira ³, Maria Madileuza Carneiro Neves ⁴, Luiz Felipe Gomes Rebello Ferreira ⁵, Marcelo Zaldini Hernandes ⁵, Jennifer de la Vega ⁶, Antônio Pereira-Neves ³, Arturo San Feliciano ⁷, Esther Del Olmo ⁶, Haiana Charifker Schindler ², Lílian Maria Lapa Montenegro ⁸

Affiliations

1 Department of Immunology, Aggeu Magalhães Institute (IAM), Oswaldo Cruz Foundation (FIOCRUZ), Recife, PE, 50.740-465, Brazil. Electronic address: [email protected].
2 Department of Immunology, Aggeu Magalhães Institute (IAM), Oswaldo Cruz Foundation (FIOCRUZ), Recife, PE, 50.740-465, Brazil.
3 Aggeu Magalhães Institute (IAM), Oswaldo Cruz Foundation (FIOCRUZ), Recife, PE, 50.740-465, Brazil.
4 Central Public Health Laboratory of Pernambuco, Dr. Milton Bezerra Sobral (LACEN-PE), Recife, PE, 52171-011, Brazil.
5 Laboratory of Medicinal Theoretical Chemistry (LQTM), Department of Pharmaceutical Sciences, Federal University of Pernambuco, Recife, PE, Brazil.
6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy-CIETUS, University of Salamanca, Salamanca, Spain.
7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy-CIETUS, University of Salamanca, Salamanca, Spain; Graduate Program in Pharmaceutical Sciences, University of Vale do Itajai, UNIVALI, Itajaí, SC, 88302-202, Brazil.
8 Department of Immunology, Aggeu Magalhães Institute (IAM), Oswaldo Cruz Foundation (FIOCRUZ), Recife, PE, 50.740-465, Brazil. Electronic address: [email protected].

PMID: 37399709 DOI: 10.1016/j.ejmech.2023.115579

Abstract

Tuberculosis remains a major public health problem and one of the top ten causes of death worldwide. The alarming increase in multidrug-resistant and extensively resistant variants (MDR, pre-XDR, and XDR) makes the disease more difficult to treat and control. New drugs that act against MDR/XDR strains are needed for programs to contain this major epidemic. The present study aimed to evaluate new compounds related to dihydro-sphingosine and ethambutol against sensitive and pre-XDR Mycobacterium strains, as well as to characterize the pharmacological activity through in vitro and in silico approaches in mmpL3 protein. Of the 48 compounds analyzed, 11 demonstrated good to moderate activity on sensitive and MDR Mycobacterium tuberculosis (Mtb), with a Minimum Inhibitory Concentration (MIC) ranging from 1.5 to 8 μM. They presented 2 to 14 times greater potency of activity when compared to ethambutol in pre-XDR strain, and demonstrated a selectivity index varying between 2.21 and 82.17. The substance 12b when combined with rifampicin, showed a synergistic effect (FICI = 0.5) on sensitive and MDR Mtb. It has also been shown to have a concentration-dependent intracellular bactericidal effect, and a time-dependent bactericidal effect in M. smegmatis and pre-XDR M. tuberculosis. The binding mode of the compounds in its cavity was identified through molecular docking and using a predicted structural model of mmpL3. Finally, we observed by transmission electron microscopy the induction of damage to the cell wall integrity of M. tuberculosis treated with the substance 12b. With these findings, we demonstrate the potential of a 2-aminoalkanol derivative to be a prototype substance and candidate for further optimization of molecular structure and anti-tubercular activity in preclinical studies.

Keywords

Antitubercular drugs; Dihydrosphingosine analogues; Ethambutol; Multidrug resistance; Mycobacterium tuberculosis.

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