Several novel thiourea derivatives of the NNRTI HI-236 substituted at the C-2 oxygen of the phenyl ring have been synthesized and evaluated for their inhibitory activity against HIV-1 (IIIB) replication in MT-2 cell cultures. The compounds were synthesized in order to fine-tune the activity of HI-236 as well as to gain insight into spatial characteristics in the pocket pertaining to the positional choice of tether in the design of [NRTI]-tether-[HI-236] bifunctional inhibitors. Two of the thiourea derivatives bearing a butynyl (6c) or hydroxyethyl tether (6n) were endowed with improved anti-HIV activity compared to HI-236. NNRTI activity was confirmed by a cell-free RT assay on six of the derivatives in which 6c returned an IC 50 of 3.8 nM compared to 28 nM for HI-236, establishing it as an improved lead for HI-236. The structure-activity profile is discussed in terms of potential interactions in the NNRTI pocket as suggested by a docking model using AutoDock, which have a bearing on the bifunctional drug design.

A combination of different HIV inhibitors into a single molecular entity is a strategy that is growing in popularity in HIV-chemotherapy research. The high levels of resistance elicited by both nucleoside and non-nucleoside reverse transcriptase inhibitors has prompted the design of double-drugs combining these two entities with the aim of addressing the emergence of resistance. The strategy involves combining two different inhibitors into a single chemical entity via a linker, with the aim of improving the physicochemical characteristics of the individual compounds. Linkers may be sub-divided into cleavable and non-cleavable. While the former result in regeneration of the parent drugs of the double-drug once in the cell cytoplasm, the latter type is designed to allow the double-drug to target two active sites in a simultaneous or bifunctional fashion, which are located in close proximity. The linkers have been attached at the C-5', C-5 or N-3 positions of the nucleoside, and in some of the substrates synthesized, a synergistic anti-HIV activity has been observed. This review focuses on the design and synthesis of anti-HIV double-drugs reported to date.

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Four double-drug HIV NRTI / NNRTI inhibitors 15a-d of the type [d4U]-spacer- in which the spacer is varied as 1-butynyl (15a), propargyl-1-PEG (15b), propargyl-2-PEG (15c) and propargyl-4-PEG (15d) have been synthesized and biologically evaluated as RT inhibitors against HIV-1. The key step in their synthesis involved a Sonogashira coupling of 5-iodo d4U's benzoate with an alkynylated tethered HI-236 precursor followed by introduction of the HI-236 thiourea functionality. Biological evaluation in both cell-culture (MT-2 cells) as well as using an in vitro RT assay revealed 15a-c to be all more active than d4T. However, overall the results indicate the derivatives are acting as chain-extended NNRTIs in which for 15b-d the nucleoside component is likely situated outside of the pocket but with no evidence for any synergistic double binding between the NRTI and NNRTI sites. This is attributed, in part, to the lack of phosphorylation of the nucleoside component of the double drug as a result of kinase recognition failure, which is not improved upon with the phosphoramidate of 15d incorporating a 4-PEG spacer.

The fight against pathogenic microorganisms has in recent decades been met with fierce setbacks owing to the antimicrobial resistance phenomenon. Conventional antimicrobials have thus weakened in their effectiveness against microbes, calling for the development of innovative strategies to combat the emerging global health crisis. A promising therapy for filling this gap is photodynamic antimicrobial chemotherapy which destroys microorganisms by making use of the combined action of a photosensitizer, light, and oxygen. The modality inactivates a wide range of pathogens, including bacteria, fungi, protozoa, and viruses. Of greater interest in photodynamic antimicrobial chemotherapy is the ability to destroy resistant strains of microbes without encouraging selection for resistance genes, thus immensely contributing to the fight against antimicrobial resistance. Different PSs vary in their microbial inactivation efficacies. Therefore, various structural modification approaches are being adopted to improve their respective activities. In this paper, recent studies focusing on strategies employed to improve the effectiveness and efficacies of PSs used in photodynamic antimicrobial chemotherapy are reviewed.