1,4–Diarylpiperazines and analogs as anti-tubercular agents: Synthesis and biological evaluation

Despite progress in modern chemotherapy to combat tuberculosis, the causative pathogen Mycobacterium tuberculosis (M.tb.) is far from eradicated. Bacillary resistance to anti-mycobacterial agents, bacillary persistence and human immunodeficiency virus (HIV) co-infection hamper current drug treatment to completely cure the infection, generating a constant demand for novel drug candidates to tackle these problems.A small library of novel heterocyclic compounds was screened in a rapid luminometric in vitro assay against the laboratory M.tb. strain H37Rv. A group of amidines was found to have the highest potency and was further evaluated for acute toxicity against C3A hepatocytes. Next, the most promising compounds were evaluated for activity against a multi-drug resistant clinical isolate. The group of amidines was also tested for their ability to kill intracellular M.tb. residing in mouse J774A.1 macrophages. Finally, we report on a correlation between the structural differences of the compounds and their anti-mycobacterial activity.

Graphical abstractSynthesis of 1,4–diarylpiperazines with increased carbon side chain length resulted in lower MIC50 against M.tb. Impact of carbon chain on anti-mycobacterial activity is assessed by different biological parameters .Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A series of heterocyclic compounds was screened by luminometry against M.tb. H37Rv. ► A piperazine core in the structure is needed for an efficient inhibition of M.tb. ► Elongation of the carbon chain increases the anti-mycobacterial activity. ► Both extracellular and intracellular replication of M.tb can be inhibited. ► Selected compounds are also active against Lam-1,a multi-drug resistant M. tb isolate.