Madher N. AlFindee

Structure–Activity Relationships for Antibacterial to Antifungal Conversion of Kanamycin to Amphiphilic Analogues

Novel fungicides are urgently needed. It was recently reported that the attachment of an octyl group at the O-4″ position of kanamycin B converts this antibacterial aminoglycoside into a novel antifungal agent. To elucidate the structure-activity relationship (SAR) for this phenomenon, a lead compound FG03 with a hydroxyl group replacing the 3″-NH2 group of kanamycin B was synthesized. FG03s antifungal activity and synthetic scheme inspired the synthesis of a library of kanamycin B analogues alkylated at various hydroxyl groups. SAR studies of the library revealed that for antifungal activity the O-4″ position is the optimal site for attaching a linear alkyl chain and that the 3″-NH2 and 6″-OH groups of the kanamycin B parent molecule are not essential for antifungal activity. The discovery of lead compound, FG03, is an example of reviving clinically obsolete drugs like kanamycin by simple chemical modification and an alternative strategy for discovering novel antimicrobials.

One-step synthesis of carbohydrate esters as antibacterial and antifungal agents

Carbohydrate esters are biodegradable, and the degraded adducts are naturally occurring carbohydrates and fatty acids which are environmentally friendly and non-toxic to human. A simple one-step regioselective acylation of mono-carbohydrates has been developed that leads to the synthesis of a wide range of carbohydrate esters. Screening of these acylated carbohydrates revealed that several compounds were active against a panel of bacteria and fungi, including Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Candida albicans, Cryptococcus neoformans, Aspergillus flavus and Fusarium graminearum. Unlike prior studies on carbohydrate esters that focus only on antibacterial applications, our compounds are found to be active against both bacteria and fungi. Furthermore, the synthetic methodology is suitable to scale-up production for a variety of acylated carbohydrates. The identified lead compound, MAN014, can be used as an antimicrobial in applications such as food processing and preservation and for treatment of bacterial and fungal diseases in animals and plants.

Tuning the biological activity of cationic anthraquinone analogues specifically toward Staphylococcus aureus

Development of new antibacterial agents against drug resistant bacteria is an imminent task, especially against methicillin-resistant Staphylococcus aureus (MRSA). While MRSA can still be treated with broad spectrum antibiotics, the use of which often leads to the disruption of normal microbial flora leading to Clostridium difficile infection (CDI). Herein, a new class of antibacterial agent, cationic anthraquinone analogues specifically against MRSA, has been developed. Through the variation and optimization of substituents, these agents are selective toward MRSA, and not Gram negative bacteria which may avoid the problem of CDI. In addition, newly discovered lead compounds also show significantly reduced cytotoxicity against normal mammalian cells than cancerous cells. This interesting finding can alleviate the toxicity and side effect problems often associate with the use of antibiotics.

Synthesis and biological activity investigation of azole and quinone hybridized phosphonates

Phosphonates, azoles and quinones are pharmacophores found in bioactive compounds. A series of phosphonates conjugated to azoles and quinones with variable carbon chain lengths were synthesized in 3-4 steps with good yield. Antifungal assay of these compounds showed that ethyl protected phosphates have excellent inhibitory activity against phytopathogenic fungus Fusarium graminearum, and the free-base phosphates have good activity against human pathogenic fungi Aspergillus flavus and Candida albicans. Structure- activity relationship (SAR) studies showed activity increases with longer carbon chain length between phosphonate and anthraquinone analogs consisting of azole and quinone moieties. These newly synthesized compounds also have mild antibacterial activities to Gram positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Cytotoxicity analysis of these compounds against HeLa cells reveals that the phosphoric acid analogs are less toxic compared to ethyl protected phosphonates. Three leads compounds have been identified with prominent antifungal activity and low cytotoxicity.