Fused Heterocycles: Synthesis of Some New Imidazo[1,2-a]- Pyridine Derivatives

Some new thiazolidines and spirothiazolidines derived from hydrazones of 2-methylimidazo[1,2-a]pyridine-3-carboxylic acid hydrazide, a bioisosteric derivative of isoniazid, were synthesized and characterized by analytical, IR, 1 Hand 13 C-NMR and mass spectral data. Some of the newly synthesized compounds were screened for their antimycobacterial activities. None of the tested compounds showed significant in vitro antituberculous activity at 6.25 µg/mL (MIC rifampin 0.031 µg/mL).


Introduction
Mycobacterium tuberculosis infects over one-third of the world's population and causes almost three million deaths every year [1].Isonicotinic acid hydrazide (isonazid) is one of the primary drugs used in combination with ethambutol, rifampin, streptomycin and pyrazinamide to treat tuberculosis, but the treatment of this disease is still a major health problem due to multi-drug resistant bacterial strains and new antimycobacterial agents, different from available first-line drugs, are urgently needed.As part of our studies on imidazo[1,2-a]pyridine we have recently reported the synthesis of some imidazo [1,2-a]pyridine-3-carboxylic acid hydrazides and related compounds and their antimycobacterial activities [2].Continuing our search for new antimycobacterial agents we have now synthesized some new ketone-hydrazones 3a-c, thiazolidines 4a-c and spiro compounds 4d-g incorporating an imidazo[1,2-a]pyridine moiety.These compounds were characterized by their elemental and spectral analyses (IR, 1 H-NMR, 13 C-NMR and mass spectra).
Condensation of 2 with the appropriate ketones in ethanol yielded the corresponding ketonehydrazones 3. The hydrazones were reacted with mercaptoacetic acid in dry benzene (Method A) to give cyclocondensation products 4b,d and e in 69.8-72.3% yields.On the other hand, refluxing a mixture of 2 and the appropriate ketone together with mercaptoacetic acid in dry benzene (Method B) also produced the target compounds 4 but in higher yields (69.7-99.1 %), except in the case of 4b (55.5 %).All the compounds were characterized by their physical data and elemental analyses (Table 1), IR, 1 H-and 13 C-NMR and EI mass spectra.The IR spectra of the starting materials 3 showed C=O bands in the 1654-1679 cm -1 region.A new strong band at 1690-1710 cm -1 in the spectra of 4 provided firm support for ring closure.The most significant evidence for the reaction was the presence of two doublets (dd, 2H, J=16 Hz) at about 3.61 and 3.68 in the 1 H-NMR spectrum of 4b [6].In the spectra of 4a,c-g, the same protons were observed as singlets (2H) at about 3.40-3.72ppm due to the lack of chirality. 13C-NMR and DEPT (135) spectra of the prototypes (4b,d and, e) were also studied and are detailed.Signals at about 71.44-76.59ppm, which are not seen in DEPT spectra, were assigned to the quarternary (spiro) carbon atoms.According to the data obtained from DEPT and HETCOR experiments the signals at about 28.80-29.72ppm were assigned to the CH 2 group located in the thiazolidine moiety [7].The mass spectra of all the compounds were relatively simple and showed (except for 4g) the peaks due to molecular ions.

Antituberculous Activity
Primary screening was conducted at 6.25 µg/mL against M. tuberculosis H 37 Rv.The M. tuberculosis H 37 Rv was grown in a medium containing a radiolabeled substrate.Labeled CO 2 produced was detected and quantitated with a BACTEC 460 automatic radiometric system.Compounds giving inhibitions < 90 % (MIC > 6.25 µg/mL, MIC rifampin 0.031 µg/mL) were not evaluated further [5].None of the compounds showed antituberculous activity at the tested concentration.

General
Melting points determined with a Buchi 530 melting point apparatus in open capillaries and are uncorrected.IR (KBr disks) and 1 H-and 13 C-NMR spectra (DMSO-d 6 ) were recorded on Perkin Elmer Model 1600 and Bruker AC 200 and DPX 400 instruments, respectively.Microanalyses were carried out on a Carlo Erba 1106 elemental analyzer.All starting materials were purchased E. Merck (Darmstadt, Germany).
2-Aminopyridine (0.01 mol) was heated under reflux with ethyl 2-chloroacetoacetate (0.1 mol) in 96 % C 2 H 5 OH (25 mL) for 6h and then cooled.Excess C 2 H 5 OH was evaporated in vacuo.The residual red oil was partitioned between ether-water.After drying, the ether extracts were evaporated and the residual oil was allowed to crystallize.M.p. 69 °C, yield 45.05%.

Method A
A mixture of 3a-c (0.01 mol) and HSCH 2 COOH (0.15 mol) was heated under reflux for 6h in dry benzene (30 mL) using a Dean-Stark trap for removal of water of condensation.Excess benzene was evaporated in vacuo.The residue was triturated with saturated NaHCO 3 until CO 2 evaluation ceased and then allowed to stand overnight.The solid thus obtained was filtered, washed with H 2 O and recrystallized from an C 2 H 5 OH-H 2 O mixture.

Table 1 .
Some physical and analytical data of compounds 3