Novel 2-hydrazino-pyrimidin-4(3H)-one derivatives with pseudofunctional- similarity to siderophores as potential antimycobacterial agents

• Published in: Medicinal chemistry (Shp-sariqah, United Arab Emirates) Vol. 9; no. 1; p. 77
• Main Authors: Bairwa, Ranjeet, Tawari, Nilesh R, Alate, Amruta, Anam, Swapnil, Degani, Mariam S, Ray, Muktikant, Rajan, Ramakrishna M G
• Format: Journal Article
• Language: English
• Published: Netherlands 01-02-2013
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Cercopithecus aethiops; Humans; Hydrazines - chemical synthesis; Hydrazines - chemistry; Hydrazines - pharmacology; Iron Chelating Agents - chemistry; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis - drug effects; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Siderophores - chemistry; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Vero Cells
• ISSN: 1875-6638
• DOI: 10.2174/157340613804488332

Siderophores are small molecules produced by bacteria under iron-scarcity conditions faced by bacteria inside host. Sideophores bind iron with high affinity (Kd < 10-25 M) and are required for iron transport into the bacterial cell. Small molecules interfering with siderophore functioning can be promising anti-mycobacterial agents. Several molecules with hydrazone as a structural feature are known to have metal chelating property. This prompted us to investigate the metal chelating ability of 2-hydrazino-pyrimidin-4(3H)-one derivatives. In this light, a library of 22 novel molecules with 2- hydrazino-pyrimidin-4(3H)-one moiety was synthesized and the compounds were evaluated against M. tuberculosis under iron-limiting and iron-rich conditions. Interestingly, several molecules showed promising (MIC: < 10 μM) selective activity under iron scarcity conditions. Furthermore, compounds were found to be nontoxic at lower concentration in VERO cell lines using MTT assay. Taken together, we have discovered novel 2-hydrazino-pyrimidin-4(3H)-one molecules active against M. tuberculosis which can be developed as potent antimycobacterial agents.