Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization

Abstract

Whole-cell high-throughput screening of a diverse SoftFocus library against Mycobacterium tuberculosis (Mtb) generated a novel aminopyrazolo[1,5-a]pyrimidine hit series. The synthesis and structure activity relationship studies identified compounds with potent antimycobacterial activity. The SAR of over 140 compounds shows that the 2-pyridylmethylamine moiety at the C-7 position of the pyrazolopyrimidine scaffold was important for Mtb activity, whereas the C-3 position offered a higher degree of flexibility. The series was also profiled for in vitro cytotoxicity and microsomal metabolic stability as well as physicochemical properties. Consequently liabilities to be addressed in a future lead optimization campaign have been identified.

The synthesis and evaluation of triazolopyrimidines as anti-tubercular agents

“…Analog 67 had comparable activity to our original hit, but analog 68 showed an MIC > 20 μM. Pyrazolopyrimidine 11 and imidazopyridine12, 13 compounds have also been reported to possess potent anti-tubercular activity. Analog 69 with a pyrazolopyrimidine core demonstrated comparable activity to original hit 1 , but with increased cytotoxicity, whereas the imidazopyrimidine-based analog 70 had excellent anti-tubercular activity as well as good separation from cytotoxicity.…”

Novel Antitubercular 6-Dialkylaminopyrimidine Carboxamides from Phenotypic Whole-Cell High Throughput Screening of a SoftFocus Library: Structure–Activity Relationship and Target Identification Studies

“…A screen of a BioFocus DPI SoftFocus library of ∼35 000 compounds against virulent Mtb H37Rv conducted at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID/NIH, U.S.) led to a number of confirmed hits, which included compound 1 with a moderate minimum inhibitory concentration (MIC) value of 20 μM in albumin–dextrose complex (ADC) medium containing ∼0.4% bovine serum albumin (BSA). The compound was slightly more potent in GAST-Fe (glycerol-alanine-salts) 20 minimal medium, likely driven by the absence of BSA which allowed for higher free concentration of the compound under the assay conditions. Hence, GAST-Fe was used alongside the 7H9/ADC medium during further SAR exploration of the series.…”

“… 19 Compounds that induce DNA damage were also excluded in order to avoid general cytotoxicity, as well as targets such as DNA gyrase whose clinically used inhibitors are exemplified by the fluoroquinolones. Along with an aminopyrazolo[1,5- a ]pyrimidine chemical series, 20 a 6-dialkylaminopyrimidine carboxamide scaffold was identified as a hit series with a potentially novel MOA, based on the initial biology triage process ( Figure 2 ). Herein, we describe the synthesis, structure–activity relationship (SAR), in vitro absorption, distribution, metabolism, and excretion (ADME), and in vivo pharmacokinetic (PK) and biological profiles of this chemical series.…”

Synthesis, evaluation, molecular docking, and molecular dynamics studies of novel N‐(4‐[pyridin‐2‐yloxy]benzyl)arylamine derivatives as potential antitubercular agents

“…Plates were read after completion of Weeks 1 and 2 using inverted enlarging mirror plate reader and graded for growth and no growth. The MIC was defined as the lowest drug concentration that prevented growth of bacteria (Barot et al, ; Kaniga et al, ; Soares de Melo et al, ).…”