Exploration of 4-aminopyrrolo[2,3-d]pyrimidine as antitubercular agents

Abstract

Tuberculosis (TB) is one of the leading causes of death worldwide. Developing new anti-TB compounds using cost-effective processes is critical to reduce TB incidence and accomplish the End TB Strategy milestone. Herein, we describe the synthesis and structure-activity relationships of a library of thirty 7H-Pyrrolo[2,3-d]pyrimidine derivatives providing insights into the contributions of different aromatic, aryl and alkyl substitution at the C-4 position of the 7-deazapurine ring. The minimum inhibitory concentration (MIC) of the compounds against the green fluorescent protein (GFP) reporter strain of Mycobacterium tuberculosis was assayed using the standard broth microdilution method, and cell toxicity was determined using the MTT assay. Sixteen compounds displayed in vitro activity against the GFP reporter strain of Mycobacterium tuberculosis with MIC₉₀ values of 0.488-62.5 µM. This study highlights the most potent derivative, N-(4-phenoxy phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine with a MIC₉₀ value of 0.488 µM and was non-cytotoxic to the Vero cell line. Moreover, all the potent compounds from this series have a ClogP value less than 4 and molecular weight < 400; thus, likely to maintain drug-likeness during lead optimisation.

Keywords: 7H-pyrrolo [2,3-d] pyrimidines; Antitubercular activity; Cytotoxicity; SAR; Tuberculosis.

Fig. 1

Structures of 7-deazupurine-based antitubercular agents and structurally related scaffolds

Fig. 2

Design strategy for 7H-pyrrolo[2,3-d]pyrimidine analogs

Fig. 3

Structures and the percentage yields of the synthesised compounds from this study

Fig. 4

Cell survival following treatment of BJ-5ta cells for 48 h with compound 11 in comparisons with the untreated control, as determined with the MTT assay (error bars = standard deviation, n = 3)

Fig. 5

Cell survival following treatment of Vero cells for 48 h with compound 11 in comparisons with the untreated control, as determined with the MTT assay using (error bars = standard deviation, n = 3)