Antituberculosis drugs: ten years of research.

This invention describes novel pyrazole compounds of formula (IV) wherein Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl; R?x and Ry? are independently selected from T-R3, or taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 1-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen; and R2, R2', and T, and R3 are as described in the specification. The compounds are useful as protein kinase inhibitors, especially as inhibitors of aurora-2 and GSK-3, for treating diseases such as cancer, diabetes and Alzehimer's disease.

Pyrazole compounds useful as protein kinase inhititors

The present invention provides a compound of formula I: or a pharmaceutically acceptable salt or mixtures thereof. These compounds are inhibitors of protein kinases, particularly inhibitors of GSK mammalian protein kinase, and more particularly inhibitors of GSK-3 mammalian protein kinase. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of utilizing those compounds and compositions in the treatment of various protein kinase mediated disorders.

Compositions useful as inhibitors of protein kinases

Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a leading cause of mortality worldwide into 21st century. The mortality and spread of this disease has further been aggravated because of synergy of this disease with HIV. A number of anti-TB drugs are ineffective against this disease because of development of resistance strains. Internationally efforts are being made to develop new anti-tubercular agents. A number of drug targets from cell wall biosynthesis, nucleic acid biosynthesis, and many other biosynthetic pathways are being unraveled throughout the world and are being utilized for drug development. In this review, socioeconomic problems in developing countries, efforts to control this disease in different individuals, the targets (known already and newly discovered), existing anti-tubercular agents including natural products and lead molecules, and the future prospects to develop new anti-TB agents are described.

Fighting tuberculosis: an old disease with new challenges.

Drugs for treating tuberculosis (TB) have been available for over half a century, and yet the incidence of disease worldwide continues to rise year by year. In 2002, the last year for which statistics are available, it is estimated that 24,000 people developed active disease and close to 5,000

New Small-Molecule Synthetic Antimycobacterials

Chloropyrimidines as a new class of antimicrobial agents.

Suitably functionalised pyrimidines as potential antimycotic agents.

Suitably Functionalized Pyrimidines as Potential Antimycotic Agents.

5-Cyano-6-(4-pyridyl)-2-thiouracil 1 has been synthesized and used as a precursor for the synthesis of mono and bicyclic pyrimidine derivatives 2-10 to evaluate their biodynamic properties. Pyrimidines, being an integral part of DNA and RNA imparts to diverse pharmacological properties, as effective bactericide, fungicide, viricide, insecticide . and meticide l - 3 • Certain pyrimidine derivatives are also known to display antimalarial 4 , antifilarial 5 and antileishmanial 6 activities. The biodynamic property of this ring system prompted us to design pyrimidine derivatives simulating pharmacophore and substituents responsible for diverse pharmacological activities. 5-Cyano-6-( 4-pyridyl)-2-thiouracil 1 was used as a precursor to synthesize various pyrimidine derivatives from the condensation-cyclization reaction of 4pyridyl carboxaldehyde, ethyl cyanoacetate and thiourea in the presence of potassium carbonate using ethanol as solvent. Alkylation of 1 with an equimolar amount of alkyl halide at 0-5°C in DMF using potassium carbonate as a base, produced 2-alkylthio4-oxo-6- (4-pyridyl)-3,4-dihydropyrimidine-5-carbo­ nitriles 2a-f while reaction with two equivalents of alkyl halide .at ambient temperature exclusively yielded 3-alkyl-2-alkylthio-4-oxo-6-( 4-pyridyl)-3,4dihydropyrimidiner- 5-carbonitriles 3a,b. Interaction of 1 with 1,2-dibromoethane in DMF in the presence of potassium carbonate led to the formation of 6-cyano7 -{ 4-pyridyl)-2,3 -dihydrothiazolo[3 ,2-a ]pyrimidin-5(11)­ one 4. Halogenation of 2-methylthio-4-oxo-6-( 4-pyridyl)3,4-dihydropyrimidine-5-carbonitrile 2a with phos­ phoryl chloride provided 4-chloro-2-methylthio-6-( 4pyridyl)pyrimidine-5-carbonitrile 5 which was highly prone to nucleophiles. Reaction of 5 with ethyl 2mercaptoacetate in the presence of base in alcohol afforded 3-amino-2-carboethoxy-6-carboethoxymethyl­ thio-4-( 4-pyridyl)thieno[2,3-dJpyrimidine 6 through tCDRl Communication No. 5799 substitutioncyclization reactions, while reaction with amine under similar reaction conditions yielded only substitution product 7. The high susceptibility of position-2 in 2a towards nucleophile, a reaction with excess of hydrazine hydrate at reflux temperature produced 2-hydrazino-4-oxo-6-( 4-pyridyl)-3 ,4-dihy­ dropyrimidine-5-carbonitrile 8 which underwent condensation-cyclization reactions in formic and acetic acid separately yielding 9a,b (Scheme I). The hydrazine 8 also on reaction with ethyl ethoxymethylenecyanoacetate and 2-carboethoxy-3,3dimethylthioacrylonitrile separately yielded 2-(3amino-4-carboethoxypyrazol-I-yl)-4-oxo-6-( 4-pyridyl)3,4-dihydropyrimidine-5-carbonitrile lOa and 2-(3amino-4-carboethoxy-5-methylthiopyrazol-I-yl)-4-oxo

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Synthesis of pyrimidine and azolopyrimidines as biodynamic agents

A convenient synthesis of 2,3- and 2,4-pyrimidinophanes (3,5,6) has been described from 6-aryl-5-cyano-2-thiouracils (1a-c). A reaction of 2-thiouracil with dibromomethane produced 2a-c, which on further interaction with dihaloalkane under basic condition produced 2,3-pyrimidinophanes (3a,b). Halogenation of 2a,c with POCl 3 led to yield respective chloropyrimidines (4a,b), which on further reaction with diaminoalkane and 1,4-phenylenediamine separately yielded 2,4-pyrimidinophanes (5a-d and 6a,b).

https://journals.sagepub.com/doi/pdf/10.3184/030823403103174227

D. N. Upadhyay

Papers

Chloropyrimidines as a new class of antimicrobial agents.

Suitably functionalised pyrimidines as potential antimycotic agents.

Suitably Functionalized Pyrimidines as Potential Antimycotic Agents.

Synthesis of pyrimidine and azolopyrimidines as biodynamic agents

A Concise Synthesis of Pyrimidinophanes from 6-Aryl-5-Cyano-2-Thiouracil†: