Structure–Activity Relationships of Pyrazolo[1,5-a]pyrimidin-7(4H)-ones as Antitubercular Agents

Abstract

Pyrazolo[1,5- a ]pyrimidin-7(4 H )-one was identified through high-throughput whole-cell screening as a potential antituberculosis lead. The core of this scaffold has been identified several times previously and has been associated with various modes of action against Mycobacterium tuberculosis ( Mtb ). We explored this scaffold through the synthesis of a focused library of analogues and identified key features of the pharmacophore while achieving substantial improvements in antitubercular activity. Our best hits had low cytotoxicity and showed promising activity against Mtb within macrophages. The mechanism of action of these compounds was not related to cell-wall biosynthesis, isoprene biosynthesis, or iron uptake as has been found for other compounds sharing this core structure. Resistance to these compounds was conferred by mutation of a flavin adenine dinucleotide (FAD)-dependent hydroxylase (Rv1751) that promoted compound catabolism by hydroxylation from molecular oxygen. Our results highlight the risks of chemical clustering without establishing mechanistic similarity of chemically related growth inhibitors.

Regioselective Suzuki–Miyaura Reactions of Ethyl 2,6-Dibromo­pyrazolo[1,5-a]pyrimidine-3-carboxylate

“…Performing the reaction in the presence of Pd2dba3/PPh3 or Pd(OAc)2/PPh3 as tandem catalysts, did not allow a good selectivity of the coupling reaction since a mixture of mono-and diarylated products was formed in both cases (Table 1, entries [11][12]. No significant effect was observed on the selectivity when Na2CO3 was replaced by Cs2CO3 or K3PO4 (Table 1, entries [13][14]. It is noteworthy that the use of a range of ligands, such as DPPF, XantPhos or XPhos did improve neither overall conversion nor the selectivity of the cross-coupling (Table 1, entries [15][16][17].…”

“…1 H NMR (300 MHz, CDCl3): δ = 9.04 (d, J = 2.3 Hz, 1H), 8.81 (d, J = 2.3 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.14-6.99 (m, 2H), 4.52 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H). 13 C NMR (75 MHz, CDCl3): δ = 161. 3, 160.5, 152.8, 147.4, 138.0, 134.0, 131.8, 130.9, 124.6, 119.3, 114.4, 113.0, 102.7, 60.9, 55.5, 14.5 1H), 7.90-7.68 (m, 4H), 4.53 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H).…”

“…2 Since its discovery, the pyrazolo[1,5-a]pyrimidine moiety exhibits a broad spectrum of biological properties, including antibacterial, 3 antimicrobial, 4 anti-inflammatory, 5 antioxidant, 6 antileishmanial, 7 antimalarial, 8 anticancer, 9 antifungal, 10 anti-tumor, 11 antiproliferative 12 and antitubercular activities. 13 Additionally, the pyrazolo[1,5-a]pyrimidine core is present as a central unit in several marketed drugs, such as zaleplon (Insomnia), indiplon (Hypnotic and sedative), 14 dinaciclib (Melanoma, chronic lymphocytic leukemia, pancreatic cancer), 15 dorsomorphin (Bone and cartilage), 16 ocinaplon (Anxiolytic, sedative and amnesiac), 17 anagliptin (Type 2 diabetes mellitus), 18 lorediplon (Insomnia) and pyrazophos (Fungicide and insecticide) (Figure 1). 19 Figure 1 Examples of marketed drugs containing the pyrazolo[1,5a]pyrimidine core.…”

Comprehensive Coverage on Anti‐mycobacterial Endeavour Reported in 2021

“…Barry and co‐workers have reported pyrazolo[1,5‐ a ]pyrimidin‐7(4 H )‐ones ( 23 , Figure 9) with good anti‐TB activity (1.20–3.13 μM) within macrophages identified through by high throughput whole‐cell screening [47] . Further, the most active compound did not inhibit the cell wall biosynthesis or perturb the iron homeostasis suggesting the different mode of anti‐TB action.…”

“…Further, this type of compound can be used as a probing tool for mycobacterial oxidative phosphorylation pathway [54] . Barry and co‐workers have reported pyrazolo[1,5‐ a ]pyrimidin‐7(4 H )‐one ( 32 ) as anti‐TB agent with MIC of 2.34 μM having good inhibition of Mtb of host macrophages [47] . McGeary et al .…”