1,2-Dihydropyrido[3,4-b]pyrazines: structure-activity relationships

Abstract

Certain derivatives containing the 1,2-dihydropyrido[3,4-b]pyrazine (1-deaza-7,8-dihydropteridine) ring system are active against experimental neoplasms in mice. The mechanism of action of these agents has been attributed to the accumulation of cells at mitosis. Identification of the structural features that are necessary for activity was accomplished by evaluation of modified 1-deazapteridines and ring and ring-opened analogues. Relative to ethyl 4-amino-1-deaza-7,8-dihydro-6-[(N-methylanilino)methyl]pteridine-2-carbamate (11) and the corresponding 6-phenyl compound (12), no antitumor activity was observed with 7,8-dihydropteridines, 3-deaza-7,8-dihydropteridines, and the corresponding heteroaromatic compounds. Also, activity was diminished or destroyed when 1-deaza-7,8-dihydropteridines were oxidized to 1-deazapteridines or reduced to 1-deaza-5,6,7,8-tetrahydropteridines. In addition, replacement of the 4-amino group with other substituents destroyed activity. The presence of a 6-substituent containing an aryl group appeared to be necessary for activity, which was increased when a methyl group was substituted at the 7-position.

New Small-Molecule Synthetic Antimycobacterials

“…SRI-3072 (Table 1, compound 20), originally synthesized as a tubulin polymerase inhibitor (92,93), was found to affect M. tuberculosis growth with a potent MIC (0.15 g/ml) and good selectivity index (SI ϭ 42) (104). Moreover, it was found to be an inhibitor of FtsZ (a bacterial tubulin polymerase homologue).…”

Pyridine Based Antitumour Compounds Acting at the Colchicine Site

“…[186] Structure-activity relationship studies indicated that the basic diaminopyridine is an essential structural requirement. [187,188] The fused dihydropyrazine increases the pyridine basicity and tolerates diverse substituents in positions 2 and 3. [189] Clinical trials with mivobulin (CI-980) showed that it lacks sufficient activity in the treatment of disseminated malignant melanoma [190] metastatic colorectal carcinoma [191] progressive malignant gliomas [192] and soft tissue sarcomas.…”

New Frontiers in the Therapy of Tuberculosis: Fighting with the Global Menace

“…The FtsZ protein is the bacterial tubulin polymerase homologue, crucial for cell division [260,261]. From this, tubulin polymerization inhibitors were tested on mycobacte rial growth [262][263][264][265] and many inhibitors were designed [266][267][268][269][270][271][272] For instance the deazaptendme derivative SRI-3072 (48) [273,274] was found to affect M tuberculosis growth with a MIC value (015 pg/mL) and remarkable se lectivity index (SI= 42) [262] Analogous deazapteridmes were reported to inhibit polymerization o f mycobacterial FtsZ protein. The antibacterial thioether-bearing compound (49) is one o f the results o f a screening for bacterial cytoki nesis inhibitors [271] Remarkably, a taxane derivative with a similar diphenylthioether moiety was also reported for its inhibition o f M tuberculosis growth [275] The anthelmintic tubulin polymerization inhibitors, albendazole (50a) or thia bendazole (50b) and related benzimidazoles (50), are weakly effective on mycobacterial FtsZ polymerization [254,276].…”