1. Discovery of highly potent antifungal triazoles by structure-based lead fusion
Wenya Wang, Shengzheng Wang, Guoqiang Dong, Wannian Zhang*. Chunquan Sheng*. Med. Chem. Commun., 2011, 2, 1066–1072
There is a tendency that the incidence of invasive and systemic fungal infections, such as invasive candidiasis, cryptococcosis and aspergillosis, has increased dramatically worldwide during the last decades. Furthermore, the mortality (per 100,000 population) associated with invasive mycosis increased by 3.4-fold from 1980 to 1997. It is mainly caused by the growing number of immunocompromised individuals due to AIDS, organ trans- plantation and chemotherapy. Candida albicans (C. albicans), Cryptococcus neoformans (C. neoformans) and Aspergillus fumigatus (A. fumigatus) are the most frequent pathogens isolated from clinical practice. Moreover, various moulds and yeasts such as Mucor, Fusarium and Zygomucetes have also emerged as new opportunistic fungi threatening patients’ life. Currently, clinically available drugs against these fungal infections contain four major types: azoles (e.g. ﬂuconazole and itraconazole), polyene macrolides (e.g. amphotericin B), allyamines (e.g. terbinaﬁne) and echinocandins (e.g. caspofungin and micafungin). They vary in chemical structures and modes of action in different biological pathways. Clinically, azoles, especially triazoles, are ﬁrst-line agents in treating fungal infections due to their advantageous properties (e.g. broad antifungal spectrum, high activity, oral applicability and chemical stability). However, their extensive use has led to the occurrence of resistant strains which greatly limited the therapeutic options. Hence, there is an emergent demand for the discovery of new antifungal azoles. Now, newer triazoles (e.g. voriconazole and posaconazole) have beenmarketed. Other triazole candidates (e.g. ravuconazole and albaconazole) are currently under development.
2. Bacterial lipid membranes as promising targets to fight antimicrobial resistance, molecular foundations and illustration through the renewal of aminoglycoside antibiotics and emergence of amphiphilic aminoglycosides
Marie-Paule Mingeot-Leclercq, Jean-Luc Décout. Med. Chem. Commun. 2016
At the end of 2015, Garneau-Tsodikova and collaborators reported the design and synthesis of seven kanamycin B derivatives. Two of these compounds, with a C12 and C14 aliphatic chain attached at the 6″-position through a thioether linkage, exhibited good anti-Gram-positive and antifungal activity, and were found to be poorer substrates than kanamycin B for several AG-modifying enzymes. They were both relatively less hemolytic than the known membrane targeting antibiotic gramicidin and the known antifungal agent amphotericin B and were not toxic at their antifungal MIC values. Their oxidation to sulfones was also demonstrated to have no effect on their activities. Moreover, they both acted synergistically with posaconazole, an azole currently used in the treatment of human fungal infections.
3. Advances in ultrasensitive mass spectrometry of organic molecules
Mathivathani Kandiah, Pawel L. Urban*. Chem. Soc. Rev., 2013, 42, 5299-5322
For example, Shen et al. validated a sensitive liquid chromatography (LC) and atmospheric pressure chemical ionization mass spectrometry method for the determination of posaconazole in human plasma. They chose APCI rather than ESI since APCI is less prone to ion suppression, and the human plasma matrix contains a lot of potential suppressants. The oral dosage of posaconazole is 800 mg per day in divided doses. Based on earlier toxicokinetic data and allometric scaling, the analytical method needed to be refined to measure concentrations as low as 5 ng mL-1 in order to accurately characterize the human plasma concentration-time profile. This LC-MS/MS method was suitable for quantifying posaconazole over a dynamic range of 5–5000 ng mL-1. It has then been used in a number of studies aimed at characterizing the pharmacokinetics of posaconazole.