[Pyrido[2,3-b]pyrazines inhibiting both erlotinib-sensitive and erlotinib-resistant cell lines, and their preparation via regioselective condensation reaction].

The EGFR inhibitor erlotinib possesses high anti-tumor effect but despite the good clinical responses in most of the cases recrudescence occures. This can be attributed to a secondary, acquired mutation causing resistance to tyrosine kinase inhibitors. In our work we were looking for small-molecule inhibitors, which simultaneously affect on the proliferation of erlotinib-sensitive PC9 cells and PC9-ER erlotinib-resistant cells.

[Application of Kohonen Self-Organizing Feature Maps in QSAR of human ADMET and kinase data sets].

QSAR predictions have been proven very useful in a large number of studies for drug design, such as kinase inhibitor design as targets for cancer therapy, however the overall predictability often remains unsatisfactory. To improve predictability of ADMET features and kinase inhibitory data, we present a new method using Kohonen's Self-Organizing Feature Map (SOFM) to cluster molecules based on explanatory variables (X) and separate dissimilar ones. We calculated SOFM clusters for a large number of molecules with human ADMET and kinase inhibitory data, and we showed that chemically similar molecules were in the same SOFM cluster, and within such clusters the QSAR models had significantly better predictability.

[Development and study of structure-activity relationship of drugs against Mycobacterium tuberculosis].

Tuberculosis is considered to be one of the major health problem not only in the less developed countries but in the economically developed countries as well. Roughly one third of the world's population are infected with Mycobacterium tuberculosis and a significant part of them are carriers of latent tuberculosis. From ten percent of these latent infections are developing the active TB disease and fifty percent of them die from the illness without appropriate treatment.

Tyrosine kinase inhibitors - small molecular weight compounds inhibiting EGFR.

Abnormally elevated EGFR kinase activity can lead to various pathological states, including proliferative diseases such as cancer. The development of selective protein kinase inhibitors has become an important area of drug discovery for the potential treatment of a variety of solid tumors such as breast, ovarian and colorectal cancers, NSCLC, and carcinoma of the head and neck. There are three small molecule EGFR kinase inhibitor drugs in clinical use (gefitinib, erlotinib and lapatinib), and several others are currently undergoing clinical development.

[Novel method for the synthesis of carboxamides from low reactivity esters: synthesis of 2-acylamino-1-benzothiophene-3-carboxamides].

We planned and prepared a kinase inhibitor focused compound library around the 1-benzotiophene core structure, but the 2-acylamino-1-benzotiophene-3-carboxylic acid ethyl ester derivatives could not be converted to amides by the traditional methods like treatment with aqueous or alcoholic ammonia solution or ammonia gas. Under mild reaction conditions we have recovered the starting materials, higher temperature and pressure resulted the formation of pure ring-closed products. We have discovered a new method where the application of lithium amide in tetrahydrofurane resulted the desired compounds in acceptable yields (67-84%).

Synthesis and characterization of novel quinazoline type inhibitors for mutant and wild-type EGFR and RICK kinases.

The development of selective protein kinase inhibitors has become an important area of drug discovery for the treatment of different diseases. We report the synthesis and characterization of a series of novel quinazoline derivatives against three therapeutically important and pharmacologically related kinases: 1) epidermal growth factor receptor (EGFR; wild type and mutant) in the field of cancer, 2) receptor-interacting caspase-like apoptosis-regulatory kinase (RICK) in the field of inflammation, and 3) pUL97 of human cytomegalovirus (HCMV). For reference purpose we have synthesized the four clinically relevant quinazolines, including the lead compounds, which we previously identified for RICK and pUL97.

A novel drug discovery concept for tuberculosis: inhibition of bacterial and host cell signalling.

The Mycobacterium tuberculosis genome encodes for eleven eukaryotic-like Ser/Thr protein kinases. At least three of these (PknA, PknB and PknG) are essential for bacterial growth and survival. PknG is secreted by pathogenic mycobacteria, in macrophages to intervene with host cell signalling pathways and to block the fusion of the lysosomes with the phagosome by a still unknown mechanism.

[Synthesis of thiophene and alpha-terthiophene derivatives with antiproliferative activity].

We have synthesised a series of known alpha-terthiophene lead molecules with PKC (protein kinase C) inhibitory activity and the compounds were tested in cell proliferation assay on EGF-RTK (epidermal growth factor receptor protein tyrosine kinase) over-expressing tumour cell line (A431). We found that two of them had excellent antiproliferative activity. We prepared a focused molecule library around the thiophene and the terthiophene scaffold and examined these compounds in cell proliferation assay on A431.

Drug discovery in the kinase inhibitory field using the Nested Chemical Library technology.

Kinase inhibitors are at the forefront of modern drug research, where mostly three technologies are used for hit-and-lead finding: high throughput screening of random libraries, three-dimensional structure-based drug design based on X-ray data, and focused libraries around limited number of new cores. Our novel Nested Chemical Library (NCL) (Vichem Chemie Research Ltd., Budapest, Hungary) technology is based on a knowledge base approach, where focused libraries around selected cores are used to generate pharmacophore models.

Synthesis of selective SRPK-1 inhibitors: novel tricyclic quinoxaline derivatives.

SR protein-specific kinase-1 (SRPK-1) has been identified as a validated target for hepatitis B virus (HBV). A series of novel tricyclic quinoxaline derivatives was designed and synthesised as potential kinase inhibitory antiviral agents and was found to be active and selective for SRPK-1 kinase. Most of these novel compounds have drug-like properties according to experimentally determined LogP and LogS values.

Improved, high yield synthesis of 3H-quinazolin-4-ones, the key intermediates of recently developed drugs.

Purine bases and their bioisosteric analogs are widely used as building blocks in combinatorial chemistry. Recently a great number of fused pyrimidine derivatives became known as potential drug molecules against various types of proliferative diseases, caused by over-expression of protein kinases. One of the most important compound families are quinazolines : e.