Pulmonary tuberculosis, caused by the pathogen Mycobacterium tuberculosis, was declared a world health emergency by the World Health Organisation (WHO) in 1993 and is among the top ten killing ...infectious diseases. A significant challenge in its treatment is the rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains to the antitubercular drug treatments currently used. The rise has been an increasing issue partially attributed to treatment noncompliance, inadequate treatment regimens, and the emergence of TB strains resistant to existing antitubercular drugs. Through the adoption of the strategy of molecular hybridisation, a series of N-aryl-2,5-dimethylpyrrole derivatives, designed as hybrids of the MmpL3 inhibitor antitubercular agents BM212 and SQ109, have been synthesised and evaluated against susceptible and drug-resistant mycobacteria strains. Several derivatives displayed submicromolar activity against M. tuberculosis strains while reporting low eukaryotic toxicity. Additionally, multiple derivatives were active against MDR and XDR strains and intramacrophagic M. tuberculosis. The MmpL3 protein is a therapeutic target for antimycobacterial drug discovery, whose 3D structure, at the time of this work, was not yet elucidated. Through a series of computational techniques, an appropriate 3D model for MmpL3 was generated and evaluated and used to analyse and optimise the binding of the hybrid derivatives previously synthesised. Computational studies suggest that the mycolic acid transporter MmpL3 is a plausible target for the N-aryl-2,5-dimethylpyrrole derivatives, which display similar conformation binding within the active pocket as BM212 and SQ109. A Virtual High-throughput Screening cascade utilising the designed homology model of M. tuberculosis MmpL3 was also performed, leading to the identification of two compounds highly active against the H37Rv strain as well as MDR and XDR strains at submicromolar concentrations. Additionally, these compounds displayed minimal eukaryotic toxicity and therefore present as attractive candidates for preclinical trials. Lastly, a series of indole derivatives was designed, synthesised, and biologically evaluated through a computer-aided structural rigidification approach of N-aryl-2,5-dimethylpyrroles. One indole derivative was identified as a hit compound, and it exhibited submicromolar activity against M. tuberculosis H37Rv strain, possessed putative intramacrophagic activity, and was highly active against MDR strains while maintaining low eukaryotic toxicity.
An exploration of the chemical space around a 2,5-dimethylpyrrole scaffold of antitubercular hit compound 1 has led to the identification of new derivatives active against Mycobacterium tuberculosis ...and multidrug-resistant clinical isolates. Analogues incorporating a cyclohexanemethyl group on the methyleneamine side chain at C3 of the pyrrole core, including 5n and 5q, exhibited potent inhibitory effects against the M. tuberculosis strains, substantiating the essentiality of the moiety to their antimycobacterial activity. In addition, selected derivatives showed promising cytotoxicity profiles against human pulmonary fibroblasts and/or murine macrophages, proved to be effective in inhibiting the growth of intracellular mycobacteria, and elicited either bactericidal effects, or bacteriostatic activity comparable to 1. Computational studies revealed that the new compounds bind to the putative target, MmpL3, in a manner similar to that of known inhibitors BM212 and SQ109.
Display omitted
•New antitubercular 2,5-dimethylpyrroles identified from a hit expansion study are reported.•Originally designed as molecular hybrids of BM212 and SQ109.•Highly active against wild-type, multidrug-resistant and intracellular M. tuberculosis.•Selective against murine macrophages and human pulmonary fibroblasts.•Bactericidal and bacteriostatic in action against M. tuberculosis.
QSAR models are widely and successfully used in many research areas. The success of such models highly depends on molecular descriptors typically classified as 1D, 2D, 3D, or 4D. While 3D information ...is likely important, e. g., for modeling ligand‐protein binding, previous comparisons between the performances of 2D and 3D descriptors were inconclusive. Yet in such comparisons the modeled ligands were not necessarily represented by their bioactive conformations. With this in mind, we mined the PDB for sets of protein‐ligand complexes sharing the same protein for which uniform activity data were reported. The results, totaling 461 structures spread across six series were compiled into a carefully curated, first of its kind dataset in which each ligand is represented by its bioactive conformation. Next, each set was characterized by 2D, 3D and 2D + 3D descriptors and modeled using three machine learning algorithms, namely, k‐Nearest Neighbors, Random Forest and Lasso Regression. Models’ performances were evaluated on external test sets derived from the parent datasets either randomly or in a rational manner. We found that many more significant models were obtained when combining 2D and 3D descriptors. We attribute these improvements to the ability of 2D and 3D descriptors to code for different, yet complementary molecular properties.
Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse ...of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram + ve and Gram-ve pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.
Display omitted
•Novel 1,5-diphenyl-pyrrole derivatives were synthesized.•The new compounds are endowed with high antibacterial activity.•The phenyl substituents at N1 and C5 of the pyrroles is essential for activity.•Protonatable guanidine/amino moieties improve the activity against Gram-ve bacteria.•Bacterial DNA gyrase was identified as a plausible target.
A series of indolyl-3-methyleneamines incorporating lipophilic side chains were designed through a structural rigidification approach and synthesized for investigation as new chemical entities ...against Mycobacterium tuberculosis (Mtb). The screening led to the identification of a 6-chloroindole analogue 7j bearing an N-octyl chain and a cycloheptyl moiety, which displayed potent in vitro activity against laboratory and clinical Mtb strains, including a pre-extensively drug-resistant (pre-XDR) isolate. 7j also demonstrated a marked ability to restrict the intracellular growth of Mtb in murine macrophages. Further assays geared toward mechanism of action elucidation have thus far ruled out the involvement of various known promiscuous targets, thereby suggesting that the new indole 7j may inhibit Mtb via a unique mechanism.
A series of N-phenyl-2,5-dimethylpyrrole derivatives, designed as hybrids of the antitubercular agents BM212 and SQ109, have been synthesized and evaluated against susceptible and drug-resistant ...mycobacteria strains. Compound 5d, bearing a cyclohexylmethylene side chain, showed high potency against M. tuberculosis including MDR-TB strains at submicromolar concentrations. The new compound shows bacteriostatic activity and low toxicity and proved to be effective against intracellular mycobacteria too, showing an activity profile similar to isoniazid.
PDF