Synthesis, Reactions and Evaluation of the Antimicrobial Activity of Some 4-(p-Halophenyl)-4H-naphthopyran, Pyranopyrimidine and Pyranotriazolopyrimidine Derivatives

A series of naphthopyran derivatives 3a–f were prepared. Reaction of 2-amino-4-(p-chlorophenyl)-7-methoxy-4H-naphtho[2,1-b]pyran-3-carbonitrile (3b) with Ac2O afforded two products, 2-acetylamino-7-methoxy-4-(p-chlorophenyl)-4H-naphtho-[2,1-b]pyran-3-carbonitrile (4) and 10,11-dihydro-3-methoxy-9-methyl-12-(p-chloro-phenyl)-12H-naphtho[2,1-b]pyran[2,3-d]pyrimidine-11-one (5) and treatment of 3b with benzoyl chloride gave the pyranopyrimidin-11-one derivative 6. While treatment of 3b with formamide afforded 11-amino-3-methoxy-12-(p-chlorophenyl)-12H-naphtho[2,1-b]pyrano[2,3-d]pyrimidine (7). Reaction of 3b with triethyl orthoformate gave the corresponding 2-ethoxymethyleneamino-7-methoxy-4-(p-chlorophenyl)-4H-naphtho-[2,1-b]pyran-3-carbonitrile (8). Hydrazinolysis of 8 in EtOH at room temperature yielded 10-amino-10,11-dihydro-11-imino-3-methoxy-12-(p-chlorophenyl)-12H-naphtho[2,1-b]pyrano-[2,3-d]pyrimidine (9), while aminolysis of 8 with methylamine or dimethylamine gave the corresponding pyranopyrimidine and N,N-dimethylaminomethylene derivatives 10 and 11. Condensation of 9 with some carboxylic acid derivatives afforded triazolopyrimidine derivatives 12–16, while reaction of 9 with benzaldehyde gave 10-benzalamino-10,11-dihydro-11-imino-3-methoxy-12-(p-chlorophenyl)12H-naphtho[2,1-b]pyrano[2,3-d]pyrimidine (17). The structures of the newly synthesized compounds were confirmed by spectral data. The synthesized compounds were also screened for their antimicrobial activity.


General
Melting points were determined on a Stuart melting point apparatus and are uncorrected. IR spectra (ν, cm −1 ) were recorded in KBr using a FT-IR 5300 spectrometer and aPerkin Elmer spectrum RXIFT-IR system. The 1 H-NMR at (300 MHz) and 13 C-NMR spectra (75 MHz) were recorded in DMSO-d 6 on a Varian Mercury VX-300 NMR spectrometer. Chemical shifts (δ) are referred to that of the solvent.
Mass spectra were measured on a Shimadzu GMMS-QP-1000 EX mass spectrometer at 70 eV. The elemental analyses were performed at the Micro Analytical Center, Cairo University, Egypt.

General Procedure: Synthesis of Pyranopyrimidine Derivatives 9 and 10
A mixture of 8 (0.41 g, 10 mmol), hydrazine hydrate (5 mL, 99%) or methylamine (10 mmol) in absolute ethanol (50 mL) was stirred for 1 hour at room temperature. The solid obtained was filtered off and recrystallized from dioxane.

Antimicrobial Assay
Inoculums of the bacterial and fungal culture were prepared. To a series of tubes containing 1 mL each of naphthopyran compound solution with different concentrations and 0.2 mL of the inoculums was added. A further 3.8 mL of sterile water was added to each of the test tubes. These test tubes were incubated for 24 hours at 37 °C and observed for the presence of turbidity. This method was repeated by changing naphthopyran compounds for the standard drugs ampicillin and ketoconazole for comparison.

Conclusions
Our interest in the synthesis of such compounds was to focus on their study as antimicrobial agents as a part of our program which aimed at the development of new heterocyclic compounds as more potent antimicrobial agents. In this paper we revealed the synthesis of some new naphthopyran, naphthopyranopyrimidine and naphthopyranotriazolopyrimidine derivatives and the antimicrobial evaluation of all the novel compounds. The structures of these compounds were elucidated on the basis of IR, 1 H-NMR, 13 C-NMR and MS data. Evaluation of the new compounds established that 3a-e, 12-14 and 16 showed improved antimicrobial activity.