Oluseye K. Onajole

Synthesis and evaluation of SQ109 analogues as potential anti-tuberculosis candidates

As part of an ongoing project to develop highly potent anti-tuberculosis therapeutics, six SQ109 derivatives were synthesized and screened in vitro for their anti-tuberculosis activity against the ATCC strain H37Rv and the extensively drug-resistant clinical strain XDR 173. Compound 16 with an extended alkene chain was the most active against both strains of Mycobacterium tuberculosis within a MIC range of 0.5-0.25 microM. Compound 12 and SQ109 were potent within a MIC range of 1-0.5 microM, whilst compound 18 displayed an activity within the MIC range of 0.5-2 microM against both Mycobacterium tuberculosis strains.

Pentacyclo-undecane derived cyclic tetra-amines: Synthesis and evaluation as potent anti-tuberculosis agents

As part of an ongoing effort to develop highly potent anti-tuberculosis agents, fourteen pentacyclo-undecane (PCU) tetra-amine compounds were synthesized and screened for their in vitro anti-mycobacterial activity against two TB strains, H37Rv and XDR 194 [an extensively drug-resistant strain of tuberculosis]. Using the broth macrodilution method, nitrofuranylamide based compounds (6a and 6b) showed almost similar activities against the H37Rv strain of Mycobacterium tuberculosis when compared with the control drug, ethambutol. N-Geranyl piperazine PCU (8a) and trans-trans farnesyl piperazine PCU (8b) were 3.2 and 3.7 times more potent than commercially available ethambutol. Both isoprenyl PCU tetra-amine derivatives and N-decyl piperazine PCU (9a) were highly active against the XDR 194 strain of tuberculosis with MICs in the range of 0.63-3.02 microM. Cytotoxicities (IC(50)) of isoprenyl based compounds (8a, 8b) and compound 9a were tested on a mammalian cell line [MDBK (Madin Darby bovine kidney epithelium)] with values of 30, 24 and 25 microM respectively.

Synthesis and NMR assignment of pentacycloundecane precursors of potential pharmaceutical agents.

The synthesis and complete NMR elucidation of eight novel pentacycloundecane (PCU) derivatives are reported. These compounds are precursors in the synthesis of PCU‐based anti‐tuberculosis (TB) agents and potential human immunodeficiency virus (HIV) protease inhibitors. Two‐dimensional (2D) NMR techniques were used to assign the NMR spectra for these compounds. Substitution of the cage molecule at (C‐8/11) further complicates the assignment, since some of the substituted alkyl chain groups overlap with the cage proton signals. The side chain heteroatoms also introduce a rare through‐space deshielding effect to some of the carbon atoms of the cage skeleton. Ring strain in the rigid cage skeleton appears to induce drastic electronic changes in some parts of the cage framework. This observation is more dramatic for the C‐4 methylene group of the cage diols and the cage ethers. Copyright

Synthesis and NMR elucidation of novel penta-cycloundecane amine derivatives as potential antituberculosis agents

The synthesis and NMR elucidation of five novel penta‐cycloundecane amine derivatives are reported. These compounds are potential antituberculosis agents. The 1H and 13C spectra showed major overlapping of methine signals of the cage skeleton making it extremely difficult to elucidate these compounds. The overlapping occurs as a result of the additions made to the carbonyl carbon (C‐8/C‐11) of the cage. The two‐dimensional NMR technique proved to be a useful tool in overcoming this problem. All compounds reported are meso compounds thereby not only simplifying the NMR structure elucidation, but also making it indeed possible. Copyright

Novel Linear Diamine Disubstituted Polycyclic ‘Cage’ Derivatives as Potential Antimycobacterial Candidates

As a part of an ongoing project to develop highly potent antituberculosis therapeutics, a series novel polycyclic ‘cage’ tetra‐amines were synthesized and screened for in‐vitro antituberculosis activities against the H37Rv strain of tuberculosis. Three disubstituted polycyclic moieties, namely pentacyclodecane, pentacycloundecane, and tricyclodecane, were used in this study. Compounds 5 and 7 showed similar activity to SQ109 at a MIC of 1 μm while compounds 4, 6 and 8 displayed MIC activity at 1 < MIC<10 μm against H37Rv strain of tuberculosis. Compounds 5, 7 and SQ109 were selected for further screening against, multi‐drug resistant, (R1097) and extensively drug resistant, (X149) strains of tuberculosis. Compound 5 showed anti‐TB activity of a MIC = 1 μm against multi‐drug resistant strain (R1097) and <1 μM against extensively drug resistant strain (X149) while compound 7 and SQ109 showed excellent anti‐TB activity against both drug‐resistant strains at a MIC <1 μm. This study demonstrates the first reported analysis of pentacyclo[5.3.0.02,5.03,9.04,8]decane as a potential therapeutic agent.

In Vitro Antifungal and Antibacterial Activities of Pentacycloundecane Tetra‐Amines

The antifungal and antimicrobial activities of three pentacycloundecane (PCU) tetra‐amine derivatives are reported herein. The in vitro activity of these PCU derivatives against yeasts (Candida albicans and non‐albicans species) and filamentous fungi was evaluated using the Clinical and Laboratory Standards Institute (CLSI) M27‐A2 and M38‐A2 guidelines and the 2H‐tetrazolium salt, (MTS) colorimetric method. The minimum inhibitory concentration against most of the tested clinical fungal strains for GKM8 and GKM9 derivatives ranges from 15.6 to 62.5 μg/mL while GKM11 ranged from 3.9 to 7.8 μg/mL. The GKM11 derivative was also active against fluconazole‐resistant strains of fungi. The GKM11 derivative also exhibited promising activity against filamentous fungi in that it was 2.5 times more active than amphotericin B against Sporothrix schenckii. Antibacterial activity was determined using the broth microdilution method (BMM) and the iodonitrotetrazolium chloride (INT) colorimetric method. The GKM11 derivative was mainly active against Gram‐positive bacteria with MIC ranging from 3.9 to 7.8 μg/mL. Activity against Gram‐negative bacteria tested was limited to Escherichia coli and Elizabethkingia meningoseptica (MIC of 31 μg/mL).

Synthesis and NMR elucidation of novel tetrapeptides

The synthesis and NMR elucidation of Ala‐Val‐Pro‐Ile and five novel peptide‐based derivatives are reported. These peptides mimic the natural second mitochondria‐derived activator of caspase (Smac) protein. Purification was achieved using preparative HPLC and the NMR elucidation of all compounds is reported for the first time. A series of overlapping signals were observed in the 1D NMR spectra thus making assignment a difficult task to undertake. The use of 2D NMR techniques with the inclusion of efficient adiabatic symmetrized ROESY proved to be an effective tool in overcoming these difficulties. Copyright

Synthesis and NMR elucidation of novel pentacycloundecane-based peptides

The synthesis and NMR elucidation of two novel pentacycloundecane (PCU)‐based peptides are reported. The PCU cage amino acids were synthesised as racemates and the incorporation of the cage amino acid with (S)‐natural amino acids produced diastereomeric peptides. The diastereomeric ‘cage’ peptides were separated using preparative HPLC and the NMR elucidation of these PCU containing peptides are reported for the first time. The 1H and 13C NMR spectra showed series of overlapping signals of the cage skeleton and that of the peptide, making it extremely difficult to resolve the structure using one‐dimensional NMR techniques only. The use of two‐dimensional NMR techniques proved to be a highly effective tool in overcoming this problem. Copyright

N-(Adamantan-1-yl)-2-chloro-acetamide.

In the title compound, C12H18ClNO, which was synthesized as part of a study into potential antituberculosis agents, the adamantine skeleton displays shorter than normal C—C bond lengths ranging between 1.5293 (18) and 1.5366 (15) Å. The structure also displays intermolecular N—H⋯O hydrogen bonding, which forms an infinite chain in the a-axis direction.

1,7-Dimethyl­penta­cyclo­[5.4.0.02,6.03,10.05,9]undecane-8,11-dione

The structure of the title compound, C13H14O2, a pentacycloundecane cage derivative, exhibits unusual Csp 3—Csp 3 single-bond lengths ranging from 1.505 (3) to 1.607 (2) Å and strained bond angles as small as 88.7 (1)° and as large as 121.0 (2)°. In this meso compound, an internal non-crystallographic mirror plane exists, bisecting the molecule. In the crystal, weak C—H⋯O hydrogen bonds link the molecules into an infinite spiral about a twofold screw axis along the [100] direction.