Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the Spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogs. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome. Parameter 1 Mtb H37Rv MIC90 (µM) 0.30 Mtb MIC90 (µM) (108 strains) 0.60 Intracellular H37Rv MIC80 (µM) 0.25 Antibacterial panel IC50 (µM) ≥16 Mammalian cell (HepG2) Tox50 (µM) 36 clogP 2.99 CLint (mL/min•g) mouse microsomes >30 CLint (mL/min•g) human microsomes 25 Solubility CLND (µM) 266 The compound's intra-macrophage activity, selectivity for mycobacteria vs. other bacterial species, and potency against a broad panel of clinical isolates including MDR and XDR strains, in vitro-cidal behavior and a low frequency of spontaneous resistance 13a suggested a highly promising antitubercular profile. The low microsomal stability was a concern and required improvement. In this paper, we report our efforts to optimize this family of compounds through the synthesis of analogs aimed at retaining the antitubercular potency while improving the overall profile for the series. RESULTS AND DISCUSSION Synthesis and In Vitro Evaluation of Analogs Aiming to explore the chemical space of the series, a library of novel compounds was synthesized and evaluated. The compounds were isolated either as free amines or as salts (hydrochloride or

No abstract

No abstract

Many Fusarium species are pathogenic, causing crop diseases during crop production and spoilage of agricultural products in both commercial and smallholder farming. Fusarium attack often results into food contamination, yield loss and increases in food insecurity and food prices. Synthetic fungicides have been used as a control strategy for the management of crop diseases caused by Fusarium pathogens. The negative effects associated with application of many synthetic pesticides has necessitated the need to search for alternative control strategies that are affordable and environmentally safe. Research on medicinal plants as control agents for Fusarium pathogens has received attention since plants are readily available and they contain wide variety of secondary metabolites that are biodegradable. The activities of solvent extracts, essential oils and compounds from medicinal plants have been tested against Fusarium phytopathogenic species. A summary of recent information on antifungal activity of plants against Fusarium species is valuable for the development of biopesticides. This paper reviews the antifungal research conducted on medicinal plants against Fusarium pathogens, over a 10-year period, from January 2012 to May 2021. We also highlight the challenges and opportunities of using natural products from medicinal plants in crop protection. Several databases (Science Direct and Web of Science) were used to obtain information on botanical products used to control Fusarium diseases on crops. Keywords search used included natural products, antifungal, Fusarium, crops diseases, phytopathogenic, natural compounds and essential oil.

No abstract

Smallholder farmers play a major role in crop production towards household food security, particularly in resource-poor communities. Maize is a common crop produced in smallholder farming and it is cultivated from seeds that has been stored and re-used for years. Spoilage of stored grains is a major challenge, which leads to yield loss and poor seed quality. The objectives of this study were to evaluate in vivo antifungal activity of selected plant extracts against Fusarium pathogens on maize seeds, and to evaluate their phytotoxicity on seed germination and seedling growth. Fresh leaves collected from eight medicinal plants were dried and selectively extracted with water, ethyl acetate or acetone. The dried extracts were evaluated for antifungal activity against Fusarium pathogens (F. proliferatum, F. oxysporum, F. subglutinans, F. verticilloides, F. semitectum, F. chlamydosporum, F. solani, F. equisite and F. graminearum) inoculated on maize seeds. Melia azedarach acetone extract showed strong antifungal activity (97% inhibition) against F. proliferatum while combined acetone extracts from Combretum erythrophyllum and Quercus acutissima exhibited 96%, 67% and 56% inhibition against F. verticilloides, F. proliferatum and F. solani, respectively. With the exception of Quercus acutissima ethyl acetate, none of the extracts significantly inhibited seed germination when compared to untreated seeds. This study showed that plant extracts could control Fusarium diseases without any adverse effects on maize seed germination or plant growth.

No abstract

No abstract