Synthesis and biological evaluation of antiparasitic Cysteine protease inhibitors based on the Isatin Scaffold

Includes bibliographical references.Widespread drug resistance, loss of efficacy and toxicity has limited the full utilization of the current available drugs against malaria and other parasitic diseases. This necessitates the development of new drugs. Meanwhile, the cysteine protease family of enzymes has been identified as potential targets for new modes of chemotherapy due to the numerous critical roles they play in the disease-causing agents. In this project, a non-peptidic and low molecular weight isatin (indole-2, 3-dione) possessing a wide range of pharmacological properties was used as a scaffold to which different moeities were appended. Potential inhibitors of parasitic cysteine proteases and three strains of P. falciparum were identified from synthesized libraries of compounds. Various N-substituted isatin derivatives were synthesized by KF/Ah03-mediated reaction of isatins with an alkyl, acyl or sulfonyl halide. A series of isatin-3-thiosemicarbazones were prepared by condensation of isatin I substituted isatins with thiosemicarbazide, and also a series of isatin-based Schiff and Mannich bases were prepared by reacting selected isatin-3-thiosemicarbazones with formaldehyde and appropriate secondary amines. To compare the effects of replacing the Mannich bases, a similar series of aminoquinolineethylene isatin-based derivatives were then synthesized. The synthesis was accomplished by condensation of quinoline-ethylene ketone forms with thiosemicarbazide. All synthesized compound were obtained in reasonable to excellent yields and characterized by spectroscopic and analytical techniques

An investigation into the biocatalytic application of the thermostable nitrile hydratase from the thermophilic strain Geobacillus pallidus RAPc8

Includes abstract.Includes bibliographical references (leaves 190-215).Nitrile hydratases (NHases) are bacterial metalloenzymes that catalyze the hydration of nitriles to their corresponding amides. The enzymes have been found in several microorganisms and participate in the metabolism of nitrile compounds as source of carbon and nitrogen. The commercial use of NHases is well recognized and has prompted research interest as well as the application of the enzymes in the manufacture of commodity amide chemicals. This has largely been due to the versatile nature of the enzymes, associated with their physiochemical properties and broad substrate specificity. However, the widespread application of nitrile-converting enzymes in the industrial processes has been restricted in part by the thermal instability of the mesophilic-derived enzymes, and thus there is an increased focus on NHases from thermophilic microorganisms. A novel moderately thermophilic microorganism, Geobacillus pallidus RAPc8, was isolated by our collaborators (Pereira and co-workers, 1998). The strain has an optimal growth temperature of 65oC and constutitively expresses a thermostable nitrile hydratase. The gene cluster containing the nitrile hydratase were cloned, sequenced, and inducibly expressed in E. coli BL21 (DE3) to levels of approximately 49 U/mg. The NHase was purified by four steps including heat treatment, ammonium sulfate precipitation, hydrophobic interaction chromatography and ion exchange chromatography

1-(5-Bromo-2-oxoindolin-3-yl­idene)thio­semicarbazide acetonitrile monosolvate

In the crystal structure of the title compound, C9H7BrN4OS·C2H3N, the mol­ecules are connected via N—H⋯O and N—H⋯S inter­actions into zigzag chains perpendicular to [001]. The mol­ecules in these chains are additionally linked to acetonitrile solvent mol­ecules through N—H⋯N hydrogen bonding. The mol­ecules are arranged in layers and are stacked in the direction of the c axis indicative of π–π inter­actions, with distance = 3.381 (7) Å for the C⋯C interaction parallel to [001]. An intra­molecular N—H⋯O hydrogen bond is also observed in the main mol­ecule

1-(5-Nitro-2-oxoindolin-3-yl­idene)thio­semicarbazide

In the title molecule, C9H7N5O3S, there is an intramolecular N—H⋯O. The molecule is essentially planar, with the maximum deviation from the mean plane of the 18 non-H atoms being 0.135 (2) Å for the amine N atom. In the crystal, the molecules are connected via intermolecular N—H⋯O and N—H⋯S hydrogen bonds, forming two-dimensional networks lying parallel to (10). They are separated by an interplanar distance of 3.3214 (9) Å, leading to π–π interactions which stabilize the crystal structure

Next-Generation Antimalarial Drugs: Hybrid Molecules as a New Strategy in Drug Design

Malaria is a disease that affects nearly 40% of the global population, and chemotherapy remains the mainstay of its control strategy. The global malaria situation is increasingly being exacerbated by the emergence of drug resistance to most of the available antimalarials, necessitating search for novel drugs. A recent rational approach of antimalarial drug design characterized as “covalent bitherapy” involves linking two molecules with individual intrinsic activity into a single agent, thus packaging dual-activity into a single hybrid molecule. Current research in this field seems to endorse hybrid molecules as the next-generation antimalarial drugs. If the selective toxicity of hybrid prodrugs can be demonstrated in vivo with good bioavailability at the target site in the parasite, it would offer various advantages including dosage compliance, minimized toxicity, ability to design better drug combinations, and cheaper preclinical evaluation while achieving the ultimate object of delaying or circumventing the development of resistance. This review is focused on several hybrid molecules that have been developed, with particular emphasis on those deemed to have high potential for development for clinical use. Drug Dev Res 71: 20–32, 2010. © 2009 Wiley-Liss, Inc