Babita Aneja

The increasing incidence of human candidiasis and the tendency of Candida species to become resistant to existing chemotherapies are well-recognized health problems. The present study demonstrates the successful synthesis of novel triazole–amino acid hybrids with potent in vitro and in vivo inhibitory activity against Candida species. Particularly, compounds 68 and 70 showed potent in vitro activity against fluconazole (FLC) resistant as well as sensitive clinical isolates of Candida albicans. Time kill curve analysis of lead inhibitors 68 and 70 showed their fungistatic nature. Secretion of hydrolytic enzymes, mainly proteinases and phospholipases, decreased considerably in the presence of 68 and 70 indicating their interference in fungal virulence. TEM analysis of Candida cells exposed to compounds 68 and 70 clearly showed morphological changes and intracellular damage as their possible mode of action. A preliminary mechanistic study carried out on the two most effective inhibitors (68 and 70) revealed the inhibition of ergosterol biosynthesis thereby causing the cells to lose their integrity and viability. The selected compounds did not show significant cytotoxicity up to a concentration of 200 μg mL⁻¹ in the HEK293 cell line. An in silico analysis of 68 and 70 binding to a modeled C. albicans CYP51 showed critical H-bonding as well as hydrophobic interactions with the important active site residues indicating the basis of their anti-Candida role. Studies on the larvae of Galleria mellonella showed that the selected inhibitors (68 and 70) were non-toxic, did not provoke an immune response and significantly reduced Candida proliferation in vivo.

Rapidly increasing resistance to the currently available antimalarial drugs has drawn attention globally for the search for more potent novel drugs with a high therapeutic index. The genome sequencing of the human malarial parasite Plasmodium falciparum has provided extensive information to understand potential target pathways and efforts are being made to develop lead inhibitors with a hope to eliminate the disease. This review is focused on a brief description of key biochemical targets identified from the genome sequence of P. falciparum. This review also summarizes the work undertaken by different scientific groups over the last five years to develop inhibitors from natural, semisynthetic or synthetic sources, which will be valuable to medicinal chemists to develop novel antimalarial agents.

Monocyclic β-lactam and unexpected oxazinone formation: synthesis, crystal structure, docking studies and antibacterial evaluation. . ???aop.label???.

Using diketoesters as the template, various derivatives were designed and the selected compounds were synthesized as bacterial methionine aminopeptidase (MetAP) inhibitors. The results of in vitro antibacterial screening revealed fifteen compounds (1a–c, 1e–h, 1j, 1l, 2a–c, 3d, 5c and 5e) as potent against different bacterial strains. By using the MTT assay on human cell line (HepG2), the viability of cell proliferation was evaluated and nine compounds (1c, 1e, 1j, 1l, 2a,b, 3d, 5c and 5e) showed no cytotoxic effect at the concentration range of 50–450 μg ml⁻¹. In the biochemical evaluation against methionine aminopeptidase (MetAPs) from Streptococcus pneumonia (SpMetAP), Mycobacterium tuberculosis (MtMetAP), Enterococcus faecalis (EfMetAP) and human (HsMetAP), compounds displayed differential behaviour against these four enzymes. Moreover, compound 1g showed 84% inhibition of SpMetAP, while compound 3d selectively inhibited MtMetAP with 79% inhibition and little effect on HsMetAP at 100 μM concentration. At the same concentration, compound 5e exhibited 87% and 85% inhibition of EfMetAP and SpMetAP, respectively. Understanding the mode of binding through modeling at the active site provided the structural basis for the possible mode of inhibition. Together, these data will be useful for further development of diketo acid based inhibitors with improved potency and selectivity.