Experimental and In-Silico Investigation of Anti-Microbial Activity of 1-Chloro-2-Isocyanatoethane Derivatives of Thiomorpholine, Piperazine and Morpholine.

Charles O Nwuche,Akachukwu Ibezim,Oguejiofo T Ujam,Ifeoma B Ujam

doi:10.1371/journal.pone.0170150

Charles O Nwuche, Akachukwu Ibezim + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0170150

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Abstract

The Antibiogram properties of 1-chloro-2-isocyanatoethane derivatives of thiomorpholine (CTC), piperazine (CPC) and morpholine (CMC) were evaluated by the approved agar well diffusion, the minimum inhibitory concentration (MIC) and in silico techniques. A total of fourteen microbial cultures consisting of ten bacteria and four yeast strains were used in the biological study while affinity of the compounds for DNA gyrase, a validated antibacterial drug target, was investigated by docking method. Results indicate that both thiomorpholine and piperazine had zero activity against the Gram negative organisms tested. With morpholine, similar result was obtained except that cultures of Escherichia coli (ATCC 15442) and Salmonella typhi (ATCC 6539) presented with weak sensitivity (7–8 mm) as shown by the inhibition zone diameter (IZD) measurement. The Gram positive organisms were more sensitive to morpholine than the other compounds. The highest IZD values of 15–18 mm were achieved except for Streptococcus pneumoniae (ATCC 49619) in which mobility of the compound stopped after 12 mm. S. pneumoniae was resistant to both thiomorpholine and piperazine. The yeast strains were not sensitive to any of the studied compounds investigated. The MIC tests evaluated against a reference antibiotic show that while morpholine was most active at 4 μg.ml-1 against both B. cereus ATCC (14579) and B. subtilis, the least active compound was thiomorpholine which inhibited S. aureus (ATCC 25923) at 64 μg.ml-1. The three compounds demonstrated high affinity for the target protein (DNA gyrase) ranging from -4.63 to -5.64 Kcal/mol and even showed better ligand efficiencies than three known antibiotics; chlorobiocin, ciprofloxacin and tetracycline. This study identified the studied compounds as potential antibiotic leads with acceptable physicochemical properties and gave the molecular basis for the observed interactions between the compounds and the target protein which can be harnessed in structural optimization process.

Highlights

There has been increased interest in antimicrobial activity of compounds derived from multifunctional heterocyclic molecules especially those from thiomorpholine [1,2,3] and piperazine [4,5,6] and morpholine [7,8,9]
In order to determine the antimicrobial activity of each synthesized compound, freshly prepared Mueller Hinton Agar (MHA) plates were seeded with 100 μL broth culture of each bacteria or yeast
CTC and CPC showed zero activity to all the Gram negative organisms tested while CMC presented with negligible antimicrobial effect against E. coli ATCC 11105 and S. typhi ATCC 6539

Summary

Introduction

There has been increased interest in antimicrobial activity of compounds derived from multifunctional heterocyclic molecules especially those from thiomorpholine [1,2,3] and piperazine [4,5,6] and morpholine [7,8,9] This is partly because they are privileged molecules for the preparation of bioactive compounds but mainly because they offer better solubility and pharmacokinetics [10,11,12,13]. Antibiotic resistance results from drug overuse especially in animal husbandry [16,17,18] and prophylaxis [19], inappropriate (incorrect or suboptimal) application during self-prescription and medication as well as widespread usage in hospitals [20] These avenues promote the selection of bacterial strains that no longer respond to treatment [21,22]. Oral bioavailability profile of the compounds was evaluated using selected molecular descriptors to avoid potential waste of resources on molecules that could pose pharmacokinetic challenge

Materials and Methods

Results and Discussion

Antimicrobial Tests Results

Conclusions