Pharmacological screening of synthetic piperidine derivatives

Abstract

Piperidine derivatives are essential heterocyclic compounds that have beneficial roles in the medical and commercial sector. They can be isolated from plant material and can be chemically synthesised using simple cost efficient methods. Piperidines and their derivatives are clinically used to prevent postoperative vomiting, facilitate radiological evaluation, correct gastrointestinal function as well as speed up gastric emptying before anaesthesia. Piperidine derivatives also demonstrate a wide spectrum of biological activities which include; antimicrobial, anticancer, anti- TB, anti-HIV, anti-inflammatory, analgesic, anti-influenza, anti-inflammatory and antitumor activity. The properties of piperidine derivatives depend on the nature of the side chains and their orientation.

Based on the promising data that demonstrated the synergistic effects of biological agents with piperidine derivatives, the aim of our research is to determine the pharmacological activities, i.e. (i) antimicrobial activity, (ii) anti-inflammatory, (iii) anti-oxidant activity, (iv) cytotoxicity, and (v) biosafety of six piperidine derivatives, PM1 to PM6.

All six piperidine derivatives (PM1-PM6) screened for antimicrobial activity exhibit characteristics of varying degrees of microbial inhibition against some Gram-positive and Gram-negative bacteria (B. cereus, B. subtilis, E. coli, S. aureus, Kl. Pneumonia, M. liuteus and P. aurenginosa) with the exception of B. polymixa, S. marcescens and S. faecalis. Certain piperidine derivatives did not demonstrate high inhibition activity towards the fungal strains, with inhibition only shown against four fungal species; A. niger, A. flavus, C. albicans and S. cerevisiae. Thus it is proposed that minor changes could be made to the structure of the compounds so that they can alter the effect that the compounds have on the specific fungi strains. With regard to antioxidant activity it is noted that the concentrations of the test compounds are directly proportional to the percentage of scavenging capacity. In comparison of the piperidine derivatives (PM1-PM6) to Rutin (reference standard), it was illustrated that Rutin displayed the best antioxidant activity. All six piperidine derivatives (PM1-PM6) showed greater than 50% anti-inflammatory activity, whilst the anti-inflammatory reference standard NCGA displayed the greatest activity in comparison to the piperidine derivatives tested. The safety of the piperidine derivatives was tested by assaying cytotoxicity, against melanoma, MCF7 cancer cells and normal fibroblasts as well as Brine shrimp lethality assay. All piperidine derivatives demonstrated high cytotoxicity activity against both cancer cell lines (melanoma and MCF7) and around 50 – 52% cytotoxicity against healthy cells. Chloro substitution of the phenyl ring increases cytotoxicity of compounds (Aerluri et al., 2012). This compound can be used in the treatment of cancer cells while inhibiting 50% of normal cells. All six piperidine derivatives (PM1-PM6) were also tested for toxicity against Artemia salina in a brine shrimp lethality assay. Piperidine derivatives exhibited varying degree of toxic activity towards the shrimp, with all derivatives displaying ± 50% toxic activity at 1000 µg/mL. These results reveal a directly proportional relationship between concentration of drug and toxicity.

It remains a future research objective to modify these piperidine compounds (PM1-PM6) chemically to produce more derivatives for further biological evaluation. All the studied piperidine compounds have possible leads for optimization to carry out pre-clinical trials. We can conclude that the substitution of different side chains on the piperidine nucleus results in varying degree of pharmacological activity. Also, compounds containing the substitution of a chloro group at position 4 and a fluoro group at position 2 on the phenyl ring attached to carbon 2 and 6 on the piperidine nucleus resulted in high pharmacological activity. This good pharmacological activity was also exhibited by compounds containing substitutions of a methoxy group at position 3 on the phenyl ring attached to carbon 1 and 6 on the piperidine nucleus. Compounds containing a methoxy group positioned at carbon 4 on the phenyl ring which is attached to carbon 1 and 4 on the piperidine nuleus presented low pharmacological activity. Low activity was also exhibited by compounds containing substitution of a cyano group at position 4 on the phenyl ring which is attached to carbon 2 and 6 on the piperidine ring and a methyl group at position 4 on the phenyl group attached to a nitrogen at position 1 on the piperidine nucleus.