Novel Pyrazole-Containing Compounds Active against Mycobacterium tuberculosis

Abstract

In this study, a series of 49 five-membered heterocyclic compounds containing either a pyridine- or a pyrrole-type nitrogen were synthesized and tested against Mycobacterium tuberculosis. Among them, only the 1,3,5-trisubstituted pyrazoles 5–49 exhibited minimum inhibitory concentration values in the low micromolar range, and some also exhibited an improved physicochemical profile without cytotoxic effects. Three pyrazoles were subjected to an animal tuberculosis efficacy model, and compound 6 induced a statistically significant difference in lung bacterial counts compared with untreated mice. Moreover, to determine the target of this series, resistors were generated, and whole genome sequencing revealed mutations in the mmpL3 gene.

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

“…Very few molecules make it through the stringent bottlenecks of TB drug discovery because finding a new anti-TB drug is challenging: new compounds should kill Mtb with novel mechanisms of action showing rapid bactericidal activity, as well as activity against bacteria in different metabolic states without host toxicity. Even though the advances in understanding the biology of Mtb, including its complete genome sequence, have provided a platform of a wide range of novel drug targets, most of the compounds discovered in the last few years repeatedly target the cell wall (MmpL3 [ 3 , 4 , 5 , 6 ], DprE1 [ 7 , 8 , 9 ], FadD32 [ 10 ], and Pks13 [ 11 ]), while most of the approximately 625 essential Mtb genes are unexploited. With the approval of bedaquiline, which targets mycobacterial energy production [ 12 ], and delamanid, which targets both cell wall synthesis and energy production, the energy-metabolism in Mtb [ 12 ] has received significant attention in the last decade as a potential target to investigate and develop new antimycobacterial drugs.…”

Identification of novel chemical scaffolds that inhibit the growth of Mycobacterium tuberculosis in macrophages

“…Previous work has identified similar pyrazole-containing compounds with anti-tubercular activity that target MmpL3. In these studies, a 1,3,5-trisubstituted pyrazole as a central core had good activity against axenically-cultured M. tuberculosis (25). Our moelcules differ in that they only have weak activity against extracellular bacteria.…”

“…tuberculosis with good acitivity of IC 50 <10 µM (Table 7). Three compounds (23)(24)(25) were cyotoxic and we could not calculate activity. Three compounds (26, 27 and 29) showed good intracellular potency with IC 50 <5 μM.…”

MmpL3 Inhibition: A New Approach to Treat Nontuberculous Mycobacterial Infections

“…Therefore, new SAR indicates only one phenyl ring at C5 is essential for the activity whereas the N1 phenyl can be replaced with an alkyl or cycloalkyl substituent. The morpholine group is optimal for activity at the C3 position [78,79]. Compound 29 has an isopropyl group at the N1 position and para-isopropylphenyl group at the C5 position along with C2-methyl and C3-methyl morpholine.…”