Antibacterials pyridazines

In 1977, a review on the antimicrobial activity of pyridazine derivatives was published [309]. Accordingly, in the present article, antibacterial pyridazines developed more than a decade ago will be mentioned only briefly. Synonyms of the agents (95)-(104) listed below are given in areference book [96]. In order... 

In addition, there are several Japanese patents on antibacterial pyridazine derivatives as represented by formulae (110, X = halogen R = substituted amino, AlkS) [320, 321], (111, R1 = substituted Ph R2 = alkyl, alkenyl, morpholinosulphonyl) [322] and (112, R1 = aryl, aminosubstituted heterocycle R2 = H, halogen, alkyl R3 = COOH R4 = aryl, aralkyl, etc.) [323]. 

The imidazolinylpyridazine 322 provides the starting point for the synthesis of several related imidazopyrimido-pyridazines (Scheme 78). These tricycles are of interest for their antibacterial and antifungal properties <1998FA113>. 

Pyridazine-derived sulphonamide antibacterials, in particular sulphamethoxypyridazine, are still the subject of extensive investigations. Thus, for instance, in volumes 82 to 108 of Chemical Abstracts, there are more than 300 abstracts of papers dealing with compound (95, R1 = MeO R2 = H), which are not included in the present review due to space limitations. Only selected examples are mentioned. 

In West Germany pyridazinium compounds as represented by formula (120, R1 = halogen, alkyl, aryl R2 = H, alkyl R3 = substituted amino R4 = substituted alkyl, cycloalkyl) have been claimed as antibacterial agents [338]. In Australia, mercapto derivatives of several nitrogen heteroaromatics including pyridazine-derived compounds (121, R = CONH2, CH2NMe2) have been prepared in a search of amplifiers of phleomycin [339] however, only low activity has been observed in this series. 

In search of novel and more effective antibacterial agents, numerous /1-lactam antibiotics bearing a pyridazine core have been synthesized mainly in Japan. Thus, the penicillin derivative (125) characterized by a 3-hydroxypyridazine-4-carboxamido subunit has been patented as a broad-spectrum bactericide [342-345] likewise, the corresponding cephalosporin analogue has been claimed in a patent [346]. 

The pyridazine ring has also been introduced as a substituent into antibacterial carbapenems (131) [364, 365],... 

Moreover, it has to be noted that many pyridazine derivatives exhibiting antibacterial activity, which are discussed in the preceding section, also have been found to possess antifungal properties [317, 318, 322, 325, 329, 333, 334, 336, 338],... 

Recent analyses of a Free-Wilsontype have included the in vitro inhibitory activity of a series of heterocyclic compounds against K. pneumonia (197). Other applications of the Free-Wilson approach have included studies on the antimycobacterial activity of 4-alkyl-thiobenzanilides, the antibacterial activity of fluoronapthyridines, and the benzodiazepine receptor-binding ability of some non-benzodi-apzepine compounds such as 3-X-imidazo-[l,2-6]pyridazines, 2-phenylimidazo[l,2-o ]pyri-dines,2-(alkoxycarbony)imidazo[2,l-p]benzo-thiazoles, and 2-arylquinolones(198-200). 

Until recently pyridazines had not been found in nature it was believed that microorganisms do not generate hydrazine or diimide, necessary for building up the pyridazine skeleton. However, Hassall and co-workers have now isolated from Streptomyces Jamaicemis antibacterial monamycins, " which are cyclohexadepsipeptides and contain as structural unit hexahydro-pyridazine-3-carboxylic acid or its substituted derivatives. 

Many pyridazines have biological activity or have been tested for their pharmacological activity. Pyridazine derivatives have been shown to possess hypotensive activity, antibacterial and antifungal... 

PHA732>. New pyrazolo[3,4-pyridazine derivatives have shown antibacterial and antifungal activities <05EJM401>. 

In CHEC-I the applications of pyridazines, cinnolines and phthalazines were briefly summarized <84CHEC-l(3B)i>. The antibacterial monamycins were cited as a rare example of naturally occurring pyridazines, while the growth retardant, herbicidal, and fungicidal activities of synthetic pyridazine derivatives are mentioned. Note was made of the hypotensive and antihypertensive activities of hydralazine and dihydralazine, and that in the cinnoline series only 3-and 4-amino derivatives exhibit biological activity. 

Kidwai and Kumar ° reported a microwave-accelerated reaction of urea 232 with phenacylbromide to yield the iminooxazoline 233 (Scheme 1.64). In this case, the total reaction time required was only 1.0-1.5 min. Patel and Fernandes prepared the 2-amino-4-substituted oxazoles 235 as precursors to novel oxa-zolo[5,4-c]pyrazoles and oxazolo[5,4-c]pyridazines, which were evaluated as antibacterial agents. Cyclization of a-bromoketones 234 with urea in refluxing DMF afforded 235 (Scheme 1.65). 

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