The Synthesis and Biological Evaluation of Novel Nitrogen Containing 6 and 7 Membered Ring Heterocyclic Compounds

Abstract

Literature reports have previously shown interesting antimicrobial activities of compounds containing the α,β unsaturated carbonyl function and various piperidone and tropanone derivatives have attracted interest. A series of ring substituted N-piperidone dieneones and a novel parent tropan-3-one were synthesized and characterized. Novel compounds along with a previously synthesized library of 1,2-benzothiazines were examined for their antifungal properties. The tropan-3-one and benzothiazines proved to be ineffective inhibitors of Saccharomyces cerevisiae growth (<20%). Dieneones of N-piperidone and N-methyl piperidone showed a wide spectrum of activities whereby the free bases are marginally more potent than their respective hydrochloride salts. Based on their potencies against S. cerevisiae a subset of dieneones were screened against Candida albicans and Aspergillus niger. Yeast cells were incubated with the compounds for 24 or 48 hours whereas A. niger cells were incubated with the compounds for 16, 24, 48 or 72 hours respectively. Generally the presence of the N-methyl group decreases potency against yeast, whilst the opposite is true in A. niger. The compounds are not as effective at inhibiting cell growth against A. niger when compared to the yeast. Compound 41n was the most potent inhibitor giving IC90 values of 1.35 x 10-3 M (S. cerevisiae) and 1.55 x 10-3 M (C. albicans), whereas compound 39n was the most potent inhibitor of A.niger growth with an MIC value of 3.6 x 10-10 M. Selected piperidone dieneones were screened for cytotoxic properties against the A549 cancer cell line using the MTS and LDH assays. Compound 41n was found to be the most cytotoxic. Potency of benzene ring substitution was para>meta>ortho. Substituents of larger volume and lower electron withdrawing properties produce more potent compounds. The 3’-iodo substituted piperidones (39n and 41n) emerged as the most promising agents from the group of compounds in respect to their antifungal and cytotoxic potencies, although the compounds were not as effective as the reference drug miconazole.