Mini Reviews in Medicinal Chemistry - Volume 5, Issue 4, 2005

While the post-genomic era could lead into new targets for antimalarial drug development, herein few successful targets including medicinals involved in those processes are presented. Further, contribution of bioinorganic chemistry has also started to make its impact in the field of pharmaceuticals. Therefore, metal chelators, selected organometallics, and metalloantimalarials that would offer potential therapeutic drugs are also discussed. Finally, a brief summary on chloroquine-resistance mechanism(s) has been included.

In this paper, the main achievements and problems of the application of all-atom molecular simulations, with particular attention for Molecular Dynamics (MD), will be critically reviewed. Starting from unfolding simulations, through biased simulations, which require a knowledge of the native state conformation, to folding studies based on the simple knowledge of the protein (or peptide) sequence, the strengths and weaknesses of theoretical approaches to the study of folding and their matching with experimental observations will be discussed. Finally, we will give a critical outlook on the possible developments of this field in the near future.

Prion diseases are of considerable importance because of the threat of a variant form of Creutzfeldt Jakob disease that has emerged in recent years. Pre-clinical diagnosis of prion diseases still remains poor and effective therapies also do not exist at present. This review examines research on possible therapeutic strategies that might have potential benefits if applied before neurodegeneration has occurred.

1,2,4-Thiadiazole is a distinctive class of small heterocyclic thiol trapping agents that serve as an interesting pharmacophore in the design of inhibitors targeting the cysteine residues of proteins. X-Ray crystal structures of enzyme-inhibitor complex indicate that the cysteine thiol reacts with the N-S bond of the thiadiazole moiety to form a disulfide bond resulting in the inactivation of the enzymes. This review addresses the medicinal chemistry and various properties of 1,2,4-thiadiazoles in their potential as new electrophilic “warheads” for targeting the cysteine residues of biomolecules (e.g, H+ / K+ ATPase), and cysteine-dependent enzymes (e.g., cathepsin B and transglutaminase).

Endothelins (ETs) are potent vasoconstrictor peptides and are associated with several disease states like pulmonary hypertension, systemic hypertension and heart failure. Endothelin-1 (ET-1) is the first member of the family and it has the receptor subtypes known as ETA and ETB. The receptors ETA and ETB are attractive new therapeutic targets for diseases associated with elevated ET-1 levels. Several studies have thus led to the discovery of selective ETA receptor antagonists as well as non-selective ETA / ETB antagonists. The preclinical and clinical studies have clearly established that these antagonists are effective in the treatment of essential hypertension, pulmonary hypertension, heart failure and atherosclerosis. The advances in this area have resulted in the FDA approval of the orally active dual antagonist Bosentan for pulmonary hypertension in 2001. This review highlights the synthesis and structure-activity of the endothelin receptor antagonists and covers the literature in this area up to 2001.

Imidazole and benzimidazole systems are presented in a large number of common therapeutics agents. They were widely used in organic and medicinal chemistry, but recently the development of N-oxide derivatives got an improvement from the point of view of its chemical and biological activity. Though we will review recent developments in chemical and biological profiles (as antitumoral, antiparasitic, antiviral and antimicrobial agents) of these heterocycle systems and the corresponding N-oxides.