In vivo potent BM635 analogue with improved drug-like properties

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.…”

Nonclassical Mechanism in the Cyclodehydration of Diols Catalyzed by a Bifunctional Iridium Complex

“…The organic fractions were dried over Na 2 SO 4 , filtered, and concentrated to give a crude orange liquid. Column chromatography (cyclohexane/ethyl acetate, 3:1, v/v) gave the desired diketone 5 …”

“…Column chromatography (cyclohexane/ethyl acetate, 3:1, v/v) gave the desired diketone 5. [21] Synthesis of 1,5-diols 1,5-Diols 2m and n were obtained by reduction of 1,5-diketones 5m and n,r espectively.1 ,5-Diketone 5n is commercially available and was used as received from Sigma-Aldrich. The synthesis of 1,5diketone 5m was carried out by following ar eported procedure.…”

MmpL3 as a Target for the Treatment of Drug-Resistant Nontuberculous Mycobacterial Infections

“…The novel classes of bactericidal MmpL3 inhibitors that have been reported in the last few years, some of which have demonstrated activity against M. tuberculosis and MABSC in vivo , highlight the therapeutic potential of this transporter in tuberculous and nontuberculous mycobacteria and provide much needed translational opportunities for the treatment of NTM infections. Future research is expected to gain further insight into the structure of MmpL3 and its variations across Mycobacterium species in order to leverage the emerging structure-activity relationship information now available for some of these compound series (Brown et al, 2011 ; Scherman et al, 2012 ; North et al, 2013 ; Li K. et al, 2014 ; Poce et al, 2016 , 2018 ; Stec et al, 2016 ; Franz et al, 2017 ; Kozikowski et al, 2017 ). Also, critical to the further development of these inhibitors will be the availability of a simple, non-radioactive, and relatively high-throughput assay to screen optimized analogs with increased activity against MmpL3.…”

“…In last 3 years, the phenotypic screening of compound libraries against NTM has yielded a number of hits with activity against MABSC, MAC, or both complexes. Interestingly, several of these compounds appear to kill NTM through the inhibition of MmpL3, an essential mycolic acid transporter present in all mycobacteria whose therapeutic potential in the treatment of M. tuberculosis infections was highlighted in a number of recent studies (Sacksteder et al, 2012 ; Kondreddi et al, 2013 ; Lun et al, 2013 ; Rao et al, 2013 ; Remuinan et al, 2013 ; Yokokawa et al, 2013 ; Li et al, 2016 , 2017 ; Poce et al, 2016 , 2018 ; Stec et al, 2016 ; Degiacomi et al, 2017 ). The availability of cidal inhibitors against this new target, some of which have already demonstrated activity in in vivo models of MABSC infection (Dupont et al, 2016 ; De Groote et al, in revision; Pandya et al, in revision), provides much-needed novel opportunities for the treatment of pulmonary NTM infections.…”