Dataset Information

Identification of Substituted Amino Acid Hydrazides as Novel Anti-Tubercular Agents, Using a Scaffold Hopping Approach.

ABSTRACT: Discovery and development of new therapeutic options for the treatment of Mycobacterium tuberculosis (Mtb) infection, particularly drug-resistant strains, are urgently required to tackle the global burden of this disease. Herein, we reported the synthesis of a novel series of N-substituted amino acid hydrazides, utilising a scaffold hopping approach within a library of anti-tubercular agents. Efficacy and selectivity were evaluated against three strains of Mtb (wild-type, isoniazid-resistant and rifampicin-resistant), and cytotoxicity against macrophages in vitro. The antibacterial activity and therapeutic index of these molecules were significantly affected by modifications with the N-substituents. Introduction of a 3,5-dinitroaryl moiety demonstrated enhanced antibacterial activity against all three strains of Mtb. In contrast, the inclusion of an imidazo [1,2-a]pyridine-3-carboxy moiety resulted in enhanced activity towards isoniazid mono-resistant Mtb relative to wild-type Mtb. Consequently, this scaffold hopping approach showed significant promise for exemplification of novel molecules with specific activity profiles against drug-resistant tuberculosis.

SUBMITTER: Brown AK

PROVIDER: S-EPMC7287914 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Indole-containing small molecules have been reported to have diverse pharmacological activities. The aromatic heterocyclic scaffold, which resembles various protein structures, has received attention from organic and medicinal chemists. Exploration of indole derivatives in drug discovery has rapidly yielded a vast array of biologically active compounds with broad therapeutic potential. Nature is the major source of indole scaffolds, but various classical and advanced synthesis methods for indoles have also been reported. One-pot synthesis is widely considered an efficient approach in synthetic organic chemistry and has been used to synthesize some indole compounds. The rapid emergence of drug-resistant tuberculosis is a major challenge to be addressed. Identifying novel targets and drug candidates for tuberculosis is therefore crucial. Researchers have extensively explored indole derivatives as potential anti-tubercular agents or drugs. Indole scaffolds containing the novel non-covalent (decaprenylphosphoryl-β-D-ribose2'-epimerase) DprE1 inhibitor 1,4-azaindole is currently in clinical trials to treat Mycobacterium tuberculosis. In addition, DG167 indazole sulfonamide with potent anti-tubercular activity is undergoing early-stage development in preclinical studies. Indole bearing cationic amphiphiles with high chemical diversity have been reported to depolarize and disrupt the mycobacterial membrane. Some indole-based compounds have potential inhibitory activities against distinct anti-tubercular targets, including the inhibition of cell wall synthesis, replication, transcription, and translation, as summarized in the graphical abstract. The success of computer-aided drug design in the fields of cancer and anti-viral drugs has accelerated in silico studies in antibacterial drug development. This review describes the sources of indole scaffolds, the potential for novel indole derivatives to serve as anti-tubercular agents, in silico findings, and proposed actions to facilitate the design of novel compounds with anti-tubercular activity.

Dataset Information

Identification of Substituted Amino Acid Hydrazides as Novel Anti-Tubercular Agents, Using a Scaffold Hopping Approach.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets