Identification of Substituted Amino Acid Hydrazides as Novel Anti-Tubercular Agents, Using a Scaffold Hopping Approach.
Alistair K BrownAhmed K B AljohaniFatimah M A AlsalemJoseph L BroadheadJason H GillYucheng LuJonathan D SellarsPublished in: Molecules (Basel, Switzerland) (2020)
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.
Keyphrases
- mycobacterium tuberculosis
- drug resistant
- wild type
- pulmonary tuberculosis
- multidrug resistant
- amino acid
- acinetobacter baumannii
- escherichia coli
- tissue engineering
- molecular docking
- magnetic resonance
- small molecule
- big data
- machine learning
- risk factors
- silver nanoparticles
- hiv aids
- molecular dynamics simulations
- electronic health record
- deep learning
- replacement therapy