Design and Synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N′-((E)-3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria

Abstract

2016)'Design and synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N-((E)-3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (SQ109) pyrrole hybrid derivatives : discovery of potent antitubercular agents e ective against multidrug-resistant mycobacteria.', Journal of medicinal chemistry., 59 (6). pp. 2780-2790. Further information on publisher's website:http://dx.doi.org/10.1021/acs.jmedchem.6b00031Publisher's copyright statement:This document is the Accepted Manuscript version of a Published Work that appeared in nal form in Journal of Medicinal Chemistry, copyright c American Chemical Society after peer review and technical editing by the publisher. To access the nal edited and published work see http://dx.doi.org/10.1021/acs.jmedchem.6b00031. Additional information:Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. out to be an excellent lead candidate for preclinical trials. In addition, four compounds showed potent inhibition (comparable to that of verapamil) towards the whole-cell drug efflux pump activity of mycobacteria, and thus turning to be promising multi-drug resistance reversal agents.

Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds

“…After, using molecular simplification, the authors have discovered the second-generation of this hybrid derivative (compound 18 ) (Figure 6) as a potent antitubercular agent with MIC 90 value of 1.58 μM. Furthermore, this compound was able to inhibit the mycobacteria drug efflux pump at potency comparable to that of verapamil [34]. …”

Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis

“…These data suggest that the presence of a secondary amine on the piperidine side chains could be beneficial for the antitubercular activity, as also observed in our previous work. [27] Finally, to prove the effectiveness of the most active compounds, their cytotoxicity was evaluated on MRC-5 and J774 cells. As a result, 12e showed a selectivity index 15 fold higher than that of TZ on MRC-5 cells (Table 3).…”

“…[27] Briefly, 200 µL of sterile deionized water was added to all outer-perimeter wells of a sterile 96-well plate (Corning Incorporated, Corning, NY) to minimize evaporation of the medium in the test wells during incubation. The wells in rows B to G in columns 3 to 11 received 100 µL of 7H9 medium containing 0.2% casamino acids, 24 µg/mL pantothenate and 10% OADC (Beckton Dickinson, Sparks, MD).…”

“…[27] In brief, early log phase cells of M. smegmatis were taken and the OD 600 was adjusted to 0.4 in 1× PBS. The test samples contained (4−6) × 10 7 bacteria/mL in PBS, 0.4% glucose (as a source of energy for efflux pumps activity), 0.5 mg/L ethidium bromide (as a substrate for efflux pumps), and the compounds being tested at 1/4× MIC concentrations.…”

Early diagnosis and effective treatment regimens are the keys to tackle antimicrobial resistance in tuberculosis (TB): A report from Euroscicon's international TB Summit 2016

“…Two generations of compounds were synthesized and interestingly the first generation of compounds turned out to be potent multidrug efflux pump inhibitors, meaning that these molecules could potentiate standard chemotherapy. 135 Dr Lee investigated derivatives such as phenyl ether and carbonate derivatives of nitroimidazole as the molecule has space to accommodate reactive groups that could improve its anti-mycobacterial profile. 136,137 Dr Roh investigated 5-substituted 2-[(3,5-dinitrobenzyl)sulfanyl]-1,3,4-oxadiazoles and 1,3,4-thiadiazoles for their excellent anti-mycobacterial activity against both susceptible and drug resistant forms of M. tuberculosis with MIC values as low as 0.03mM.…”