br Acknowledgement The authors would like to thank the

Acknowledgement The authors would like to thank the University of Johannesburg and the National Research Foundation for the financial support. Mr. D Harris and Dr. R Meyer from Shimadzu South Africa are thanked for their technical support. Prof Ian Dubery is thanked for access to the LC-MS instrument. A portion of the research was performed using the Environmental Molecular Sciences Laboratory (EMSL), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research and located at Pacific Northwest National Laboratory (PNNL) in Richland WA, USA. The NWChem calculations were performed using the Cascade supercomputer at the EMSL. Portions of this research were supported by the PNNL Laboratory Directed Research and Development program and are a contribution of the Microbiomes in Transition (MinT) Initiative. PNNL is operated by Battelle for the DOE under contract DE-AC05-76RL0 1830.
Human immunodeficiency virus (HIV) integrase inhibitors are a new component to the anti-HIV chemotherapy pharmacy, the current treatment for acquired immunodeficiency syndrome (AIDS). This class of compounds inhibits the integration of the viral PD128907 HCl receptor into the host’s and thus the infectious process. Although integrase inhibitors have been well received, new problems have recently been identified., The rapid emergence of several viral strains resistant to one or more of the drugs currently available or in trials for the treatment of AIDS has now become the most important issue in the treatment of HIV infection. We recently discovered HIV integrase inhibiting compounds of general structure as shown in . We had previously found that pyridoxine or pyridoxal phosphates could serve as an efficient backbone scaffold for the synthesis of such inhibitors albeit by an unknown mechanism of action.
Factors, such as the emergence of drug-resistant HIV-1 strains, inherent drug toxicity and problems with patient adherence, make the development of new and potent anti-HIV-1 drugs a continuing challenge. Most of the available anti-retroviral drugs, developed since the initial report of the acquired immunodeficiency syndrome (AIDS), target two of the critical HIV-1 viral enzymes, viz., protease (PR) or reverse transcriptase (RT)., , However, during the last decade, HIV-1 integrase (IN), which is responsible for integration of pro-viral cDNA into the genome of the host cell,, , has become a promising target for drug design. Extensive research has resulted in the identification of numerous small molecules as HIV-1 integrase inhibitors; these include the three compounds, raltegravir , elvitegravir and dolutegravir (), which have been approved by the FDA as integrase inhibitors. The mode of action of these drugs involves the selective inhibition of strand transfer during the integration process by complexing the two catalytic (Mn or Mg) ions in the HIV-1 IN active site. Unfortunately, clinical studies have revealed that viral mutants especially N155H, G148H and double mutant G148h G140S are resistant to both raltegravir and elvitegravir,, , and use of dolutegravir as a monotherapy has recently been discouraged. Continuation of the search for further classes of new-generation HIV-1 IN inhibitors remains a priority and we have recently described an application of the Morita-Baylis-Hillman reaction in the synthesis of 3-[(-cycloalkylbenzamido)methyl]-2-quinolones as potential HIV-1 integrase inhibitors. We now report the preparation, bioassay and HIV-1 IN receptor-site docking of readily accessible 4-arylimino-3-hydroxybutanoic acids. The target molecules – were isolated as the racemic products in good to excellent (71–87%) yields following reaction of the substituted benzaldehydes – with 4-amino-3-hydroxybutanoicacid in a mixture of ethanol and acetic acid under reflux conditions (). The structures of the novel products were confirmed by HRMS and NMR spectroscopic analysis, the latter confirming their essential purity. In photochemical studies of Fe(III) complexes, Baldwin and co-workers have reported the preparation of the dichloro derivative under basic conditions, using NaHCO and NaCl in MeOH-HO.