title: Experimental and In-Silico Investigation of Anti-Microbial Activity of 1-Chloro-2-Isocyanatoethane Derivatives of Thiomorpholine, Piperazine and Morpholine.
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.
authors.affiliation: Department of Microbiology, University of Nigeria, Nsukka, Enugu State, Nigeria.|Japan International Research Center for Agricultural Sciences (JIRCAS), Tsukuba, Ibaraki, Japan.
authors.forename: Charles O
authors.initials: CO
authors.lastname: Nwuche
authors.affiliation: Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka, Enugu State, Nigeria.
authors.forename: Oguejiofo T
authors.initials: OT
authors.lastname: Ujam
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, University of Nigeria, Nsukka, Enugu State, Nigeria.
authors.forename: Akachukwu
authors.initials: A
authors.lastname: Ibezim
authors.affiliation: Department of Pharmacognosy, University of Nigeria, Nsukka, Enugu State, Nigeria.
authors.forename: Ifeoma B
authors.initials: IB
authors.lastname: Ujam
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D003198:Computer Simulation; D006090:Gram-Negative Bacteria / Q000187:drug effects; D017953:Isocyanates / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D017953:Isocyanates; D009025:Morpholines; D010879:Piperazines; C028971:thiamorpholine; C037574:morpholine