Coumarins antibiotic activity

Chakraborty DP, Sen M, Bose PK (1961) On the Antibiotic Activity of Some Natural Coumarins. Trans Bose Res Inst 24 31... 

Reviews of saturated oxygen heterocycles <00JCS(P1)1291>, routes to 2,2-dimethyl-2H-[l]benzopyrans <00H(53)1193> and pyranonaphthoquinone antibiotics <00T1937>, HIV-1 active Calophyllum coumarins <00H(53)453> and of the application of (3-halovinylaldehydes in heterocyclic synthesis <00H(53)941> have appeared. 

Hypoprothrombinemia may occur in malabsorption syndromes and also the use of broad-spectrum antibiotics may produce a hypoprothrombinemia that responds readily to small doses of vitamin K. In premature infants and in infants with hemorrhagic disease of the newborn the use of vitamin K may be indicated. However, the main indication for the use of vitamin K is to antagonize the anticoagulant activity of coumarins. Oral absorption of phytonadione and the menaquinones is by the lymph while menadione and its water-soluble derivatives are absorbed directly. The absorption of phytonadione is energy-dependent and saturable. Intravenous administration of phytonadione has produced flushing, dyspnea, chest pains, and cardiovascular collapse. 

The enolic hydroxyl group on the coumarin moiety behaves as a rather strong acid (pKa 4.3) and is the group by which the commercially available sodium and calcium salts arc formed. The phenolic -OH group on the benzamido moiety also behaves as an acid but is weaker than the former, with a pKa of 9.1. Disodium salts of novobiocin have been prepared. The. sodium salt is stable in dry air but loses activity in the presence of moisture. The calcium salt is quite water insoluble and is used to make aqueous oral suspensions. Because of its acidic characteristics, novobiocin combines to form salt complexes with basic antibiotics. Some of the.se saits have been investigated for their combined antibiotic effect, but none has been placed on the market, as they offer no advantage. 

The antibacterial activity of a number of synthetic 3-acylamino-4-hydroxycoumarin derivatives [92] and of several other coumarins has been describe [93, 94]. However, as the carbamoyl group is of great importance to novobiocin activity, it may be that the activity of coumarin is not directly related to the activity of the antibiotic. 

Aminocoumarin antibiotics such as novobiocin, clorobiocin, and coumermycin A1 are derived from different Streptomyces species and show a very potent antibacterial activity by inhibition of DNA gyrase. Gyrase inhibitors block DNA replication, induce the SOS repair system, and eventually cause bacterial cell death (Figure 6.32) [151-154], These antibiotics possess a 3-amino-4-hydroxy-coumarin and a substituted deoxysugar noviose as common feature, which is essential for their biological activity. The biosynthetic gene clusters for novobiocin, chlorobiocin, and coumermycin A1 have been cloned in Streptomyces coelicolor M512 [155,156]. 

---