Synthesis and cytotoxic evaluation of some novel 3-[2-(2-phenyl-thiazol-4-yl)-ethyl]-3H-pyrido[2,3-d]pyrimidin-4-one derivatives.

BACKGROUND AND PURPOSE: Pyridopyrimidine and its derivatives have a variety of chemical and biological significances. Thiazole-containing compounds have also been reported to have a wide range of biological activities. Due to the valuable cytotoxic effects of both thiazole and pyridopyrimidinone derivatives, a series of pyridopyrimidinone-thiazole hybrids were synthesized in the present study. EXPERIMENTAL APPROACH: Briefly, different acyl chlorides were reacted with 2-amino nicotinic acid followed by anhydride acetic to give the corresponding pyridobenzoxazinones. The aminothiazole derivative G was also prepared via a multistep procedure and incorporated into the benzoxazinones to furnish the target pyridopyrimidinone, K1-K5. Furthermore, the cytotoxic activity of the final compounds was determined against MCF-7 and HeLa cell lines using MTT assay. FINDINGS/RESULTS: The results indicated that aromatic substitution on C2 of pyridopyrimidine nucleus was in favor of cytotoxic activity on both cell lines, of which, compound K5 bearing a chlorophenyl group showed the highest cytotoxicity. CONCLUSION AND IMPLICATIONS: The results of the present study are valuable in terms of synthesis of hybrid molecules and also cytotoxic evaluations which can be useful for future investigations about the design of novel pyridopyrimidinone-thiazole hybrids possessing better cytotoxic activities.

Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides.

The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure-activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery.

Synthesis of some new quinazolinone derivatives and evaluation of their antimicrobial activities.

WIDE RANGE OF QUINAZOLINONE BIOLOGICAL PROPERTIES INCLUDING: antibacterial, anticancer, and anti-inflammatory activities encouraged us to synthesis some fused quinazolinone derivatives. Anthranilic acid was condensed with chloro acylchloride followed by dehydration to form the benzoxazinone intermediate; subsequent addition of an amine provided the fused quinazolinones. Deoxyvasicinone which was previously synthesized by a multi step complex reactions was prepared in three steps using the following procedure: Log P values of the compounds were measured using the shake flask method in octanol/water solvent system. The synthesized compounds were evaluated against six strains of bacteria (three Gram-positive and three Gram-negative) and three strains of fungi. Overall results of antimicrobial tests showed that the compounds had better bacteriostatic activity against Gram-negative bacteria. The obtained results of MBC revealed that these compounds had more significant bacteriostatic than bactericidal activities. Almost all of the screened compounds showed good activity against C. albicans and A. niger. The obtained results of MFC indicated that these compounds had more significant fungistatic than fungicidal activities.