APPLICATIONS SUBSTITUTED 2-AMINOTHIOPHENES IN DRUG DESIGN

Highly substituted thiophene derivatives are important heterocycles found in numerous biologically active compounds. Title compounds are attractive derivatives because their applications in pharmaceuticals, agriculture and pesticides. They exhibit antimicrobial activity against various Gram(+) and Gram(-) bacteria and fungi. Many of these molecules act as allosteric enhancers of A1-adenosine receptor, glucagon antagonists as well as antioxidant and anti-inflammatory agents.


Introduction
The chemistry of 2-aminothiophenes has received much attention upon their convenient availability through the most versatile synthetic method developed by Gewald and his co-workers (GEWALD et al., 1988,).There are four basic variations originally described by Gewald and co-workers and about up to fifteen modifications to accomplish the synthesis of highly functionalized 2-aminothiophenes (SABNIS et al., 1999;GRONOWITZ and HÖRNFELDT, 2004).The improvements of the Gewald synthesis are based in diminution of the reaction time using microwave technology (HUANG et al., 2005, HESSE et al., 2007).The recent information of synthesis of title compounds is reviewed in our recent chapter (PUTEROVÁ and KRUTOŠÍKOVÁ, 2009).This article details about the use of substituted 2aminothiophenes in the synthesis of thieno-type heterocycles as a group of precursors applied in pharmaceuticals and in drug design.

Synthesis of pharmaceuticals and drugs
The ultimate positions of substituted 2-aminothiophenes in the field of drug design and synthesis of pharmaceuticals comes from their advantageous properties -the thiophene ring as is bioisosteric replacement for phenyl group broadly present in an active drugs, the thiophene core exists in many natural and synthetic pharmaceuticals.Moreover, they act as active precursors in broad range of synthetic pathways towards compounds used in therapy and biodiagnostic (JARVEST et al., 1999;DORÉ et al., 2004).

5-Substituted 2-aminothiophenes as A 1 adenosine receptor allosteric enhancers
Adenosine is an important endogenous tissue-protective compound released during ischemia, hypoxia or inflammation.Four receptor subtypes (A 1 , A 2A , A 2B , A 3 ) have been defined based on pharmacological properties (LINDEN, 1997).Considerable effort has been directed towards developing therapeutic agents targeting these receptors (BRUNS and FERGUS, 1990).Substituted 2-aminothiophenes of structure 1 -4, with alkyl, aryl and cycloalkyl substituents in C-4 and C-5 position and aroyl substituent in C-3 position (Fig. 1), maintained the best allosteric enhancer activity (NIKOLAKOPOULOS et al., 2006;FERGUSSON et al., 2008).The significant effort in the area of synthetic aminothiophene-based allosteric enhancer is directed to development and synthesis of adenosine receptor agonists with limited side-effects.Since the active compounds with potential and utility are substituted 2-aminothiophenes their synthesis in principal based on the Gewald reaction.

Synthesis thieno[2,3-d][1,3]oxazin-4-ones as inhibitors of Human Leukocyte Elastase
A series of thieno[2,3-d][1,3]oxazin-4-ones 8a -h was synthesized and evaluated in vitro for inhibitory activity toward Human Leukocyte Elastaze (HLE).The strategy presented by authors (GÜTSCHOW and NEUMAN, 1998;GÜTSCHOW et al., 1999) is base on the replacement of the benzene ring in benzoxazinones by thiophene.The study demonstrates the versatility of 2-aminothiophenes prepared by Gewald reaction as a synthetic entry to serine protease-inhibiting, fused 1,3-oxazin-4-ones.The synthetic route to novel thieno [2,3-d][1,3]oxazin-4-ones 8a -h using alkyl 2aminothiophenecarboxylates 5a,b as substrates exhibits a facile three step synthesis, as is presented on Scheme 21.Aminothiophenes 5a,b were converted to isothiocyanato- Extracellurar HLE is a serine protease contained in the azurophilic granules of human neutrophils and has been shown to contribute to the pathogenesis of destructive lung diseases, such as pulmonary emphysema, cystic fibrosis, adult respiratory distress syndrome and inflammatory disorders such as rheumatoid arthritis.For that reason, much attention is focused on the inhibition of HLE by low-molecular-weight inhibitors that might serve as therapeutic agents.

Synthesis of 3-deazathiamine
Authors (HAWSKEY et al., 2001) outlined the synthesis of 3-deazathiamine (13) in ten chemical steps, through key intermediate substituted 2-aminothiophene 9. On the Scheme 2 we have outlined the synthesis of target compound 13 starting from appropriate aminothiophene 9. Deamination of aminothiophene 9 via the bromide and following cleavage with Zn in acid media to afford derivative 10 was very efficient, displaying none of side reactions.Conversion of formed ester 10 to final 3deazathiamine (12) was accomplished in four subsequent steps isolating the crucial intermediates -aldehyde 11 and nitrile 12.The readily available and inexpensive starting materials and reagents, and the lack of protection and de-protection steps make this synthesis very fashionable (Scheme 2).
Deazathiamine diphosphate (deaza-TDP) is an analogue of thiamine diphosphate (TDP), the biologically active for of thiamin (vitamin B 1 ), with a neutral thiophene replacing positively charged thiazolium ring.TDP is co-enzyme present in a number of enzymes, including pyruvate decarboxylase, transketolase, pyruvate oxidase.Scheme 2. Reaction sequence towards 3-deazathiamine 13.
The RNA polymerase holoenzyme is a proven target for antibacterial agents.A high-throughput screening program based on this enzyme from Staphylococcus aureus had identified a 2-ureido-thiophene-3-carboxylate 18 (Fig. 5) as a low micromolar inhibitor.It displayed good antibacterial activity against S. aureus and S. epidermidis.Based on these observations the authors (AHRIN et al., 2006) reported a facile synthesis of the number of analogs of 18 via the Gewald reaction and evaluated for cytotoxic activity against Rifampicin-resistant S. aureus.A novel class of thiophene-derived antagonists of the human hepatic glucagon receptor (hGCRG) has been discovered (DUFFY et al., 2005).The synthesis of derivatives based on the lead structure 19 (Fig. 6) was accomplished using the Gewald reaction.The further investigations of such structures are challenging in development of therapeutics of the diabetes mellitus.Diabetes mellitus is a condition characterized by chronically elevated levels of blood glucose caused by incorrect function of the hormone responsible for the hGCRG activation.Because the structure-based drug design program through substituted 2aminothiophenes has been investigated broadly, up to this date there are many other research works dealing with the synthesis, pharmacology and application of thiophenebased structures in medicinal chemistry (KOUROUNAKIS et al., 2000).It is no doubt, that this area of Gewald-like thiophene derivatives exhibits the highest progress in a scope and utilization.

Conclusions
In this short review the importance of substituted 2-aminothiophenes in the medicinal chemistry was extended in terms of drug design and synthesis of pharmaceuticals.The scope of this work does not include all of the publications in this field, but the most interesting studies in the subject areas are considered.The further detailed information in the latter aspects can be found within the list of the references.