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Synthesis and Antimycobacterial and Antiprotozoal Activities of Some Novel Nitrobenzylated Heterocycles

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Synthesis and Antimycobacterial and Antiprotozoal Activities of Some Novel Nitrobenzylated Heterocycles Synthesis and Antimycobacterial and Antiprotozoal Activities of Some Novel Nitrobenzylated Heterocycles Agata G´orskaa, Lidia Chomiczb, Justyna Zebrowska˙ b, Przemysław Myjakc, Ewa Augustynowicz-Kope´cd, Zofia Zwolskad, Janusz Piekarczyke, Henryk Rebandelf, and Zygmunt Kazimierczuka,g a Institute of Chemistry, Agricultural University, 159C Nowoursynowska St., 02-787 Warsaw, Poland b Department of Medical Biology, Medical University of Warsaw, 73 Nowogrodzka St., 02-018 Warsaw, Poland c Department of Tropical Parasitology, Medical University of Gdansk, 9b Powstania Styczniowego St. 81-106 Gdynia, Poland d National Tuberculosis and Lung Diseases Research Institute, 26 Płocka St., 01-138 Warsaw, Poland e 2nd Department of Maxillofacial Surgery, Medical University of Warsaw, 4 Lindleya St., 02-005 Warsaw, Poland f Department of Teaching and Effects of Education, Medical University of Warsaw, 4 Oczki St., 02-007 Warsaw, Poland g Laboratory of Experimental Pharmacology, Polish Academy of Sciences Medical Research Center, 5 Pawinskiego St., 02-106 Warsaw, Poland Reprint requests to Prof. Z. Kazimierczuk. E-mail: [email protected] Z. Naturforsch. 61b, 101 – 107 (2006); received October 7, 2005 A series of N-, S-, and O-mononitro- and dinitrobenzyl derivatives of heterocycles was synthe- sized by alkylation of heterocyclic bases with the respective nitrobenzyl chlorides. Of the newly syn- thesized compounds, dinitrobenzylsulfanyl derivatives of 1-methyl-2-mercaptoimidazole (2c) and of 5-nitro- and 5,6-dichloro-2-mercaptobenzimidazole (8b and 8c, and 8e and 8f, respectively) showed considerable antimycobacterial activity. On a molar basis, nine of the novel compounds showed also a considerably higher antiprotozoal efficacy than metronidazole that reduced T. hominis viability to 73.5% at 8 µg/ml. Key words: Nitrobenzyl Derivatives, Antimycobacterial Activity, Antiprotozoal Activity, Trichomonas hominis Introduction The standard treatment for TB as recommended by WHO is a multidrug regimen that includes four Tuberculosis (TB) is a growing global health prob- antibiotics: rifampicin, isoniazid (INH), pyrazinamid, lem in terms of both disease burden and resistance and either streptomycin or ethambutol. This treatment to conventional chemotherapy. Nearly one–third of scheme is usually effective against M. tuberculosis. the world population is infected with Mycobacterium However, it may fail in settings with high frequency tuberculosis. This concerns both the developing and of drug resistance, resulting in markedly lowered cure well-developed countries. The World Health Organi- rate [1]. For instance, if an M. tuberculosis strain is zation estimated that over 8 million new cases ap- resistant to rifampicin and INH, the effectiveness of peared in 2002, and the global incidence rate of TB the standard treatment decreases by 15 to 77% [2]. was growing by about 1.1% per year. An important Despite enormous work done in genetics and biology aspect of the epidemic is also the rise in the occur- of this bacterium, practically no new clinically useful rence of multidrug-resistant strains of M. tuberculo- drug against this disease was developed over the last sis. Infections due to mycobacteria other than tuber- 40 years. Therefore, there is an urgent need for de- culosis (MOTT), ‘synergy’ of mycobacterial and HIV signing, synthesis, and testing of new potential anti-TB infections, and mycobacterial infections in immuno- agents. compromised patients add to the complexity of the Most recent studies of novel compounds of benz- issue. imidazole ‘ancestry’ revealed that the nitrobenzylsul- 0932–0776 / 06 / 0100–0101 $ 06.00 c 2006 Verlag der Zeitschrift f¨ur Naturforschung, T¨ubingen · http://znaturforsch.com 102 A. G´orska et al. · Nitrobenzyl Derivatives fanyl substituent in position 2 of the benzimidazole ing candidate for the synthesis of modified derivatives core especially enhanced antimycobacterial activity in as prospective drugs against M. tuberculosis and T. ho- 5-methylbenzimidazole and in benzimidazoles carry- minis. The results of the present study offer some hints ing no substituent in the benzene ring [3 – 5]. It also for the search of novel candidate drugs among con- has been found that 4,6-dichloro- and 4,6-dibromo- geners of the heterocyclic systems presented. 2-(p-nitrobenzylsulfanyl)benzimidazoles showed high efficacy against some Gram-positive bacteria [6]. Hav- Results and Discussion ing this in mind we synthesized a number of hetero- cycles carrying the most promising S-nitrobenzylated The S-substituted heterocyclic compounds studied substituents. were obtained by the alkylation of compounds 1, 3, We decided to check as well the activity in vitro of 5, 7 and 9 with the appropriate nitrobenzyl chlorides the newly synthesized nitrobenzyl derivatives against (Scheme 1). While alkylation of 3 and 9 were per- the protozoan species Trichomonas hominis (also formed in a water-acetone or water-ethanol mixture, in called Pentatrichomonas hominis). The flagellate re- the presence of K2CO3 as base, to give 4a – b and 10a – sides as a trophozoite in the distal part of small intes- c, respectively, “phase transfer” conditions were em- tine and in large intestine in humans; no cyst stage is ployed to prepare compounds 2a – c, 6a – c and 8a – f. known. While the parasite is cosmopolitan by nature, it The products were obtained in good or satisfactory is more common in the subtropical and tropical zones. yields; however, flash chromatography was needed to Infections with T. hominis were reported in persons of both sexes and all ages. However, because of pre- vailingly fecal-oral transmission route, the flagellate is found more often in children than in adults. T. hominis is often identified in human diarrheic stools. Severe T. hominis-associated diarrhea cases have been reported in newborns and children up to 5 years of age, some of which were caused by mixed infections with this and other protozoa, including Entamoeba histolytica, Giardia intestinalis and Blastocystis hominis [7 – 12]. A rare case was also described of a mixed infection with T. hominis, oral bacteria, and an oral protozoan Trichomonas tenax in pus from a subhepatic abscess in a patient with perforated penetrating ventricular ul- cer [13]. Whereas infections with T. hominis are even more common than those with Giardia intestinalis in some world regions, an optimal treatment for the former has not been defined yet. The drug used widely for many protozoan anaerobic parasites is metronida- zole (chemical name: 1-(2-hydroxyethyl)-2-methyl-5- nitroimidazole), which is also recommended to fight intestinal trichomonosis. Due to increased use of the agent, many metronidazole-resistant strains of Clostridium, Helicobacter pylori, Entamoeba histolyt- ica, Trichomonas vaginalis and Giardia intestinalis emerge, which are reported more and more frequently (see [14 – 18]). Therefore, there is a growing need for new antiprotozoal agents. In this study we tested numerous nitrobenzyl deriv- atives of heterocyclic compounds to find a hetero- cyclic core structure that would be the most promis- Scheme 1. Table 1. Some physicochemical data of nitrobenzylated heterocycles. A. G´ ◦ 1 Compound Formula (m. w.) Yield (%) M. p. ( C) R f H NMR [D6]-DMSO δ [ppm] UV solvent (v/v), λmax [nm], (ε) orska 2a C11H11N3O2S 60 83 – 84 (A) 0.45 3.50 (s, Me), 4.60 (s, CH2), H2O/MeOH (1:1): 270, (2900); (249.29) 7.20 – 8.20 (3 m, H-arom. and H-imid.) 0.1M HCl/MeOH (1:1): 265 (5000) et al. a 2b C11H10N4O4S 68 207 – 208 (A) 0.41 3.40 (s, Me), 4.60 (s, CH2), H2O/MeOH (1:1): 248 (6300); (294.28) 6.90 – 8.60 (4 m, H-arom. and H-imid.) 0.1M HCl/MeOH (1:1): 243 (11500) · Nitrobenzyl Derivatives 103 2c C11H10N4O4S 76 98 – 100 (A) 0.45 3.40 (s, Me), 4.50 (s, CH2), H2O/MeOH (1:1): 249 (5700); (294.28) 7.00 – 8.70 (4 m, H-arom. and H-imid.) 0.1M HCl/MeOH (1:1): 247 (9000) 4a C11H10N4O4 65 180 – 181 (B) 0.55 2.30 (s, Me), 5.50 (s, CH2), H2O/MeOH (1:1): 270 (6000); (262.22) 7.30 and 8.20 (2 d, H-arom.) 8.50 (s, H-imid.) 0.1M HCl/MeOH (1:1): 257 (9000) b 4b C11H9N5O6 50 178 – 179 (B) 0.39 2.30 (s, Me), 5.50 (s, CH2), H2O/MeOH (1:1): 252 (7900), 307 (6500); (243.22) 8.50 (s, H-imid.), 8.60 and 8.80 (2 m, H-arom.) 0.1M HCl/MeOH (1:1): 307 (9100), 343 (16500) 6a C13H13N3O2S 39 105 – 108 (C) 0.76 2.40 (s, 2 × Me), H2O/MeOH (1:1): 250 (5200), 276 (5100); (275.33) 4.50 (s, CH2), 7.00 (s, H-pir.), 7.70 and 8.20 (2 d, H-arom.) 0,1M HCl/MeOH (1:1): 252 (7400), 282 (6900) 6b C13H12N4O4S 90 148 – 149 (C) 0.59 2.40 (s, 2 × Me), H2O/MeOH (1:1): 247 (7800); (320.32) 4.80 (s, CH2), 7.00 (s, H-pir.), 8.10 – 8.70 (3 m, H-arom.) 0.1M HCl/MeOH (1:1): 249 (12200) 6c C13H12N4O4S 73 142 – 145 (C) 0.62 2.40 (s, 2 × Me), H2O/MeOH (1:1): 254 (5900); (320.22) 4.60 (s, CH2), 7.00 (s, H-pir.), 8.60 and 8.70 (d, m, H-arom.) 0.1 M HCl/MeOH (1:1): 250 (10000) 8a C14H10N4O4S 29 124 – 126 (A) 0.38 4.70 (s, CH2), H2O/MeOH (1:1): 264 (7 100), 319 (5 000); (330.32) 7.80 – 8.50 (5 m, H-benz. and H-arom.), 13.30 (s, H-N) 0.1 M HCl/MeOH (1:1): 262 (21 800), 304 (10 300); 0.1 M NaOH/MeOH (1:1): 276 (13 600), 396 (10 500) 8b C14H9N5O6S 28 176 – 179 (A) 0.38 5.00 (s, CH2), H2O/MeOH (1:1): 244 (5 600), 336 (4 800); (375.32) 7.50 – 8.90 (5 m, H-benz.
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