Here we have developed an effective metal-free dehydrogenative coupling method wherein α-oxyalkyl and alkyl radicals were generated from various ethers and alkanes to undergo coupling with a variety of electron-deficient heteroarenes such as un/substituted iso-quinolones, quinolines, pyridines, pyrazines and pyrimidines. The persulfate-acetone-water system was optimized for the dehydrogenative coupling with cyclic ethers which gave moderate to excellent yields of α-oxyalkyl containing heteroarenes. We have also optimized the conditions for coupling with cyclic alkanes and alicyclic ethers and demonstrated by conducting the reactions with a variety of electron-deficient heteroarenes. Further, the present method is also applicable to electron deficient arenes like naphthoquinones and moreover, it didn't require any external acid.

A metal-free and operationally simple N-arylation of NH-sulfoximines with aryne precursors is reported. Transition metal-free reaction conditions and shorter reaction times are the highlights of the present method. The mild optimized condition was also found to be suitable with enantiopure substrates.

The nitroimidazole scaffold has attracted great interest in the last decade, which ultimately led to the discovery of the successful drug Delamanid for multi-drug resistant tuberculosis (MDR-TB). Herein, we report medicinal chemistry on a 6-nitro-2,3-dihydroimidazooxazole (NHIO) scaffold with SAR on the novel series of triazolyl- and isoxazolyl-based NHIO compounds. In the present study, 41 novel triazolyl- and isoxazolyl-based NHIO compounds were synthesized and evaluated against Mycobacterium tuberculosis (MTB) H37Rv. The active compounds with MIC of 0.57-0.13 μM were further screened against dormant, as well as against resistant strains of MTB. Based on the overall in vitro profile, five compounds were studied for in vivo oral pharmacokinetics, wherein two compounds: 1g and 2e showed a good PK profile. In in vivo efficacy studies in the intra-nasal model of acute infection, 1g showed 1.8 and 1 log CFU reduction with respect to the untreated and early control, respectively. The lead compound 1g also showed an additive to synergistic effect in combination studies with first line-TB drugs and no CYP inhibition. From the present studies, the compound 1g represents another alternative lead candidate in this class and needs further detailed investigation.

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Novel polar functionalities containing 6-nitro-2,3-dihydroimidazooxazole (NHIO) analogues were synthesized to produce a compound with enhanced solubility. Polar functionalities including sulfonyl, uridyl, and thiouridyl-bearing NHIO analogues were synthesized and evaluated against Mycobacterium tuberculosis (MTB) H 37 Rv. The aqueous solubility of compounds with MIC values ≤0.5 μg/mL were tested, and six compounds showed enhanced aqueous solubility. The best six compounds were further tested against resistant (Rif R and MDR) and dormant strains of MTB and tested for cytotoxicity in HepG2 cell line. Based on its overall in vitro characteristics and solubility profile, compound 6d was further shown to possess high microsomal stability, solubility under all tested biological conditions (PBS, SGF and SIF), and favorable oral in vivo pharmacokinetics and in vivo efficacy.

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Whole-cell screening of 20,000 drug-like small molecules led to the identification of nitrofuranyl methylpiperazines as potent anti-TB agents. In the present study, validation followed by medicinal chemistry has been used to explore the structure−activity relationship. Ten compounds demonstrated potent MIC in the range of 0.17−0.0072 μM against H 37 Rv Mycobacterium tuberculosis (MTB) and were further investigated against nonreplicating and resistant (Rif R and MDR) strains of MTB. These compounds were also tested for cytotoxicity. Among the 10 tested compounds, five showed submicromolar to nanomolar potency against nonreplicating and resistant (Rif R and MDR) strains of MTB along with a good safety index. Based on their overall in vitro profiles, the solubility and pharmacokinetic properties of five potent compounds were studied, and two analogues, 14f and 16g, were found to have comparatively better solubility than others tested and acceptable pharmacokinetic properties. This study presents the rediscovery of a nitrofuranyl class of compounds with improved aqueous solubility and acceptable oral PK properties, opening a new direction for further development. KEYWORDS: Mycobacterium tuberculosis, MTB H 37 Rv, multidrug resistant-TB, 6-nitro-2,3-dihydroimidazooxazole, structure−activity relationship T he emergence of resistant tuberculosis has been a serious concern worldwide that has reinvigorated drug discovery efforts in search of novel candidates that are effective against both susceptible and resistant strains as well as safe and potentially faster-acting, with the aim of shortening lengthy TB treatments.1−3 Whole cell screening is an attractive approach to the fast identification of novel compounds active against TB. 4 The success of the whole cell screening-driven approach to tuberculosis is best illustrated by the discovery of bedaquiline (TMC207, diarylquinoline derivative). 5,6 Similar success has been shown by the discovery of other preclinical candidates such as benzothiazoles TCA-1 7 and imidazopyridine amides Q-203. 8 Considering the high attrition rate in clinical trials, further enrichment of the clinical pipeline is greatly needed.To discover novel and potent anti-TB agents, a whole-cell screening approach was adapted, and 20,000 small drug-like compounds were procured and screened. 9 The aim of this approach was to find drug-like compounds in this collection and then to chemically modify these compounds to improve their PK/PD behaviors. The library was initially screened against sensitive (H 37 Rv) and rifampicin resistant (Rif R ) strains of MTB at the concentration of 16 μg/mL, and 707 molecules demonstrated >90% growth inhibition. A minimum inhibitory concentration (MIC) determination for these compounds yielded 233 molecules with ≤8 μg/mL MIC against sensitive and resistant strains of MTB. The chemical clustering of these hits revealed nitrofuranyl methylpiperazine as one of the most potent scaffold (Figure 1). The identified nitrofuranyl methylpiperazine cluster included six co...

Mycobacterium tuberculosis bacteria cause deadly infections in patients [Corrected]. The rise of multidrug resistance associated with tuberculosis further makes the situation worse in treating the disease. M. tuberculosis proteasome is necessary for the pathogenesis of the bacterium validated as an anti-tubercular target, thus making it an attractive enzyme for designing Mtb inhibitors. In this study, a computational screening approach was applied to identify new proteasome inhibitor candidates from a library of 50,000 compounds. This chemical library was procured from the ChemBridge (20,000 compounds) and the ChemDiv (30,000 compounds) databases. After a detailed analysis of the computational screening results, 50 in silico hits were retrieved and tested in vitro finding 15 compounds with IC₅₀ values ranging from 35.32 to 64.15 μM on lysate. A structural analysis of these hits revealed that 14 of these compounds probably have non-covalent mode of binding to the target and have not reported for anti-tubercular or anti-proteasome activity. The binding interactions of all the 14 protein-inhibitor complexes were analyzed using molecular docking studies. Further, molecular dynamics simulations of the protein in complex with the two most promising hits were carried out so as to identify the key interactions and validate the structural stability.