Quinacillin

Conditions have been established where the deactivation of the beta-lactamase from Staphylococcus aureus PC1 by the penicillin substrate, quinacillin, is close to complete but fully reversible. The temperature-dependence of the rate of re-activation indicated a half-life of about 170 min for the deactivated state at 0 degrees C. Measurement of the relative viscosity of mixtures of enzyme and quinacillin at 8.4 degrees C ruled out any significant difference in shape or solvation between the deactivated and the normal enzyme. C.d. measurements of the deactivated protein, separated from excess quinacillin, showed that the quinacillin side-chain chromophore was bound in an asymmetric environment. The ellipticity associated with the bound quinacillin chromophore decreased with the same first-order rate constant as that for reappearance of enzyme activity. These findings support the accumulation of a deactivated state that contains bound quinacillin or a derivative. Quinacillin caused a 3-fold increase in the rate of 3H exchange-out (at a rate that was low compared with that for the substantially unfolded or expanded protein). However, there was rapid exchange-out of about 50 3H atoms on addition of 1 M-urea to the deactivated enzyme, whereas the same concentration had no effect on the exchange-out of 3H from native enzyme. The interpretation that quinacillin increases the susceptibility of the native state to unfolding in the presence of urea is supported by the demonstration that SO4(2)- ions decreased the rate and extent of deactivation but had no effect on the rate of re-activation, as predicted from the observation that SO4(2)- ions, in competition with urea, stabilize the native state relative to the partially unfolded state H [Mitchinson & Pain (1985) J. Mol. Biol. 184, 331-342].

The importance of the quinoxaline framework is exemplified by its presence in the well-known drugs such as varenicline, brimonidine, quinacillin, etc. In the past few years, preparation of a variety of organic compounds containing the quinoxaline framework has been reported by several research groups. The chloroquinoxalines were successfully used as substrates in many of these synthetic approaches due to their easy availability along with the reactivity especially towards a diverse range of metal and transition metal-catalyzed transformations including Sonogashira, Suzuki, Heck type of cross-coupling reactions. The transition metals e.g., Pd, Cu, Fe and Nb catalysts played a key role in these transformations for the construction of various CX (e.g., CC, CN, CO, CS, CP, CSe, etc) bonds. These approaches can be classified based on the catalyst employed, type of the reaction performed and nature of CX bond formation during the reaction. Several of these resultant quinoxaline derivatives have shown diverse biological activities which include apoptosis inducing activities, SIRT1 inhibition, inhibition of luciferace enzyme, antibacterial and antifungal activities, cytotoxicity towards cancer cells, inhibition of PDE4 (phosphodiesterase 4), potential uses against COVID-19, etc. Notably, a review article covering the literature based on transition metal-catalyzed reactions of chloroquinoxalines at the same time summarizing the relevant biological activities of resultant products is rather uncommon. Therefore, an attempt is made in the current review article to summarize (i) the recent advances noted in the transition metal-catalyzed reactions of chloroquinoxalines (ii) with the relevant mechanistic discussions (iii) along with the in vitro, and in silico biological studies (wherever reported) (iv) including Structure-Activity Relationship (SAR) within the particular series of the products reported between 2010 and 2022.

The effect of antibody on the reversible deactivation of the beta-lactamase (penicillin amino-beta-lactamhydrolase, EC 3.5.2.6) from Staphylococcus aureus has been studied using quinacillin and cephaloridine as substrates. The latter has been shown to exhibit the characteristics of an A-type substrate Citri, N., Samuni, A. and Zyk, N. (1976) Proc. Natl. Acad. Sci. U.S.A. 73, 1048-1052) and reversibly to lower the activity of the enzyme towards benzylpenicillin in a manner analogous to quinacillin. Both divalent and monovalent antibodies reduce the activity of the lactamase to 60% of the native value in the absence of substrate. The reduction by monovalent antibody is slow (t1/2 approximately equal to 25 min). Both divalent and monovalent antibodies modify the time-course of reversible deactivation independently of being added before or subsequent to deactivation by substrate. The full recovery of activity is delayed in the case of quinacillin and accelerated for cephaloridine. The activity against benzylpenicillin in the deactivated states is unaffected. These effects are shown to reflect the changed rates of hydrolysis of the two substrates in the presence of antibody. The effect of antibody is mediated by minor conformational change. Continuous assays for following the hydrolysis of quinacillin and cephaloridine by optical rotation are reported.