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

• Published in: European journal of medicinal chemistry Vol. 258; p. 115579
• Main Authors: Linhares, Leonardo Aquino, dos Santos Peixoto, Aline, Correia de Sousa, Luanna de Angelis, Lucena Laet, João Paulo, da Silva Santos, Aline Caroline, Alves Pereira, Valeria Rêgo, Carneiro Neves, Maria Madileuza, Ferreira, Luiz Felipe Gomes Rebello, Hernandes, Marcelo Zaldini, de la Vega, Jennifer, Pereira-Neves, Antônio, San Feliciano, Arturo, Olmo, Esther Del, Schindler, Haiana Charifker, Montenegro, Lílian Maria Lapa
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05-10-2023
• Subjects: Antitubercular Agents - chemistry; Antitubercular drugs; Dihydrosphingosine analogues; Drug Resistance, Multiple, Bacterial; Ethambutol; Ethambutol - pharmacology; Humans; Microbial Sensitivity Tests; Molecular Docking Simulation; Multidrug resistance; Mycobacterium tuberculosis; Sphingosine - pharmacology; Tuberculosis; Tuberculosis, Multidrug-Resistant - drug therapy; Tuberculosis, Multidrug-Resistant - microbiology; Dihydrosphingosine analogues; Antitubercular drugs; Ethambutol; Mycobacterium tuberculosis; Multidrug resistance
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115579

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.
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•A series of dihydrosphingosine and ethambutol analogues demonstrated good activity against sensitive and MDR Mtb.•12b when combined with rifampicin, showed a synergistic effect.•Induction of damage to cell wall integrity has been observed with 12b.•Binding these compounds with a protein essential to maintain the mycobacterial wall (mmpl3) has been modeled.•These 2-aminoalkanol derivatives represent promising new antitubercular agents.