Identification and Repurposing of Trisubstituted Harmine Derivatives as Novel Inhibitors of Mycobacterium tuberculosis Phosphoserine Phosphatase

Abstract

Mycobacterium tuberculosis is still the deadliest bacterial pathogen worldwide and the increasing number of multidrug-resistant tuberculosis cases further complicates this global health issue. M. tuberculosis phosphoserine phosphatase SerB2 is a promising target for drug design. Besides being a key essential metabolic enzyme of the pathogen’s serine pathway, it appears to be involved in immune evasion mechanisms. In this work, a malachite green-based phosphatase assay has been used to screen 122 compounds from an internal chemolibrary. Trisubstituted harmine derivatives were found among the best hits that inhibited SerB2 activity. Synthesis of an original compound helped to discuss a brief structure activity relationship evaluation. Kinetics experiments showed that the most potent derivatives inhibit the phosphatase in a parabolic competitive fashion with apparent inhibition constants ( K i ) values in the micromolar range. Their interaction modes with the enzyme were investigated through induced fit docking experiments, leading to results consistent with the experimental data. Cellular assays showed that the selected compounds also inhibited M. tuberculosis growth in vitro. Those promising results may provide a basis for the development of new antimycobacterial agents targeting SerB2.

Targeting amino acid metabolism of Mycobacterium tuberculosis for developing inhibitors to curtail its survival

“…Compounds 88, 91, 95, and 122 inhibited the enzyme with K i ranging from 1.75 to 18.3 μM and with MIC 99 of 0.8-6.3 μM. 77 3.16 | Cysteine metabolism 5 0 -Adenosinephosphosulphate reductase (encoded by gene, cysH) produces reduced sulphur metabolites.…”

Anti‐Tubercular Insights of Carbolines – A Decade Critique

“…It was found that β‐carbolines are also active against M. tuberculosis strain H37Rv in vitro with MIC value ranging from 0.8 to 6.3 μM (Table 7). Via such promising findings, new anti‐mycobacterial agents targeting serB2 have been produced [56] …”

“…In conclusion, the final step involves the phosphoserine phosphatase (PSP or SerB2) dephosphorylates L‐3‐Phosphoserine into L‐Serine. (Figure 17) The anti‐tubercular activity in the phosphoserine phosphatase SerB2 pathway has been demonstrated by natural compounds like harmine and harmine‐derivatives [56] …”

“…(Figure 17) The anti-tubercular activity in the phosphoserine phosphatase SerB2 pathway has been demonstrated by natural compounds like harmine and harmine-derivatives. [56] because of its inhibition profile, in vitro anti-bacterial activity, and lack of cytotoxicity. [19] Mariana and collaborators conducted such a study on the production focused on the development of β-carboline derivatives as anti-tubercular agents.…”

“…Via such promising findings, new antimycobacterial agents targeting serB2 have been produced. [56] MIC 50 value for the first and second-line treatment drugs rifampin and ciprofloxacin, respectively, and the cytotoxicity of the drug doxorubicin against Vero cells are reported as a reference. [NC-No Cytotoxicity up to 4.76 μg/mL; NT-Not Tested]…”