Antimicrobial activity of some pyridazinoquinoline derivatives

Ab.~tract : Some pyridazinoquinoline derivatives have been synthesized and screened for their possible antimicrobial activity. Com pound lc exhibited significant activity against S. aureus, ld and If exhibited significant activity against E. coli; whereas Ia and lb exhibited pronounced activity against fungi C. albicana.

Quinoline derivatives constitute an important class of heterocyclic molecules. Various substituted quinolines are reported to elicit a wide range of biological activities 1 . The immunity developed by malaria parasites against almost all the available drugs, urged the scientific community to look for newer derivatives possessing significant activity against such dreaded parasites. In our search for the synthesis of some biologically active heterocycles, we report herein some pyridazinoquinoline derivatives possessing anti-bacterial and anti-fungal activity.

Results and discussion
The title compounds were synthesized from our laboratory as per the reported procedure 2 . The screening of the compounds for activity against microorganisms has been made on the basis of their solubility in DMSO. It has been observed that lc exhibited almost comparable activity with respect to Chloramphenicol against Staphylococcus au reus, whereas ld and 1f exhibited significant activity against E. coli. Further, the screening of la and lb for antifungal activity against Candida albicans using Clotrimazole as the standard exhibited pronounced activity (Table 1). Decrease in the concentration level below 1000 J..Lg/mL, prevented its activity. Analysis of the activity data with respect to the structure reveals that the two ends of the molecule as indicated in structure 1 govern the activity and is absolutely dependent on the relative polarizability of the molecule. For Staphylococcus aureus presence of the -N0 2 group in the meta position of aromatic ring-B deactivates the molecule and thus the activity of the molecule is Jess than that of the unsubstituted molecule. On the contrary, the relative polar-izability of the molecule is more when the N0 2 group is not placed in meta position of the aromatic ring-B. The substitution on para positions of both ring~ neutralizes each other polarizability and thus the molecule behaves at par with the unsubstituted molecule. This evidently suggests that the directional polarizability in connection with the activity could have been enhanced with the substitution of electron releasing group in one of the ring there by establishing the donoracceptor concept. Unfortunately, the molecules with similar substitutions were insoluble in DMSO.
Analysis ofthe activity with respect to the different substitutions shows a linear relation as per the Hammett plot for both S. aureus and E. coli. However, for Candida albic· ana neither the unsubstituted one nor compounds with both p-substitutions displayed any activity. This further, emphasizes two factors, (i) presence of -N0 2 group in para positions of both the ring A and B cancel the polarization and behaves as ifthe molecule is unsubstituted; (ii) for Candida albicana substitution at meta position enhances the activity quite significantly.

Materials and methods :
Synthesis of the title compound (1) : General procedure : To a mixture of amyl nitrate (0.06 mol) and HCI (5 mL) at 0 °C, substituted/unsubstituted aniline in amyl alcohol was added under stirring. To the resulting mixture a solution of · 2-methyl-4-oxoquinoline (0.05 mol) in 5 N NaOH solution (20 mL) was added and stirred for 30 min. The reaction mass was neutralized with ice-cold solution of 5 N HCJ, the resulting solid was collected, washed with water and recrys-J. Indian Chern. Soc., Vol. 83, July 2006 tallized from ethanol. To the synthetic quinoline derivatives (0.01 mol) in benzene (50 mL) was added phenylpropiolic acid (0.0 I mol) and was refluxed for 8 h. Removal of the solvent gave a solid which was recrystallized from ethanol to give the desired product.
The individual chemicals to be tested were weighed and dissolved in DMSO to prepare a clear solution, to make a concentration of I 000 jlg/mL. They were sterilized by filtration using satorious 0.22 mm cellulose membrane filters.
Ph 1 Chloramphenicol solution was prepared by dissolving it in ethanol to give a final solution of concentration 1000 j.Lg/mL. This was used as standard chemical against the bacteria species. Clotrimazole solution was prepared by dissolving it in ethanol to make a concentration of 1000 j.Lg/mL. The zone of inhibition for each chemical was determined by using cup plate method as described in the litera-ture3.