Synthesis and antiprotozoal activity of mono- and bis-uracil isatin conjugates against the human pathogen Trichomonas vaginalis
Graphical abstract
Synthesis and anti-trichomonas activity of uracil-isatin conjugates.
Introduction
Human trichomoniasis is caused by Trichomonas vaginalis. This protozoal infection is the most common chronic non-viral infection and is responsible for approximately 248 million cases each year, being more prevalent than either chlamydia or gonorrheal infections.1, 2 Trichomoniasis has a ubiquitous distribution especially in under-developed countries with a combination of poor sanitation, hygiene and tropical climate. Malodorous vaginal discharge, vulval irritation, inflammation and cervical micro hemorrhages are the common symptoms which may lead to serious health complications such as infertility, preterm delivery, low birth weight and cervical cancer.3, 4 Despite its high prevalence, trichomoniasis is neglected compared to other sexually transmitted diseases and was long regarded as a self-clearing infection.5, 6 The importance of trichomoniasis has further increased dramatically because of its strong association with the increased risk of acquisition and transmission of human immunodeficiency virus (HIV).7, 8, 9, 10 Metronidazole has been the main-stay for the treatment of trichomoniasis for more than 40 years,11 however recent disclosures of genotoxicity, gastric mucus irritation and developed of clinical resistant isolates have provided strong impetus for the development of novel, non-cytotoxic and efficient scaffolds against trichomoniasis.12, 13, 14, 15, 16
Isatin (1H-indole-2,3-dione) is a chemical scaffold present widely in both human and other mammalian tissues and is also found to be a common structural motif in a variety of dyes, agrochemicals and pharmacologically active compounds.17 The synthetic versatility of isatin makes it an ideal platform for structural alteration and derivatization. This observation has been confirmed by its enormous biological potential with myriad activities such as anticancer,18 antidepressant,19 anticonvulsant,20 antifungal,21 anti-HIV,22 and anti-angiogenic properties.23 Further, it can function as a potent inhibitor of DNA gyrase, the enzyme which catalyzes the introduction of negative supercoils in a closed circular DNA.24 Note-worthy examples of 2-oxoindole analogues include SU11248 (Sutent), a 5-fluoro-3-substituted isatin derivative, was approved by the FDA in 2006 for the treatment of advanced renal carcinoma and gastrointestinal stromal tumors.25 C5- and C6-substituted isatin analogues were revealed to be selective inhibitors of monoamine oxidase B (MAOB) with 5-(4-phenylbutyl) isatin exhibiting the highest activity and being 18,500-fold more potent than isatin.26
Uracils are also considered important scaffolds in drug discovery with a wide range of biological activities, synthetic expediency and ability to confer drug like properties to the compound libraries appended on them at the N1, N3, C5 and C6 positions.27 Apart from their antiviral and anti-tumor potential, uracil analogs also possess herbicidal, insecticidal and bactericidal activities.28 Inhibition of a key step in viral replication pathways form the basis of their anti-viral potential resulting in potent activities against HIV, hepatitis B and C (HBV and HCV), the herpes viruses (HSV-1 and -2), Epstein Barr virus (EBV), and human cytomegalovirus (HCMV).29 5-fluorouracil is widely used as an anti-metabolism drug in the treatment of malignancies including primarily colorectal, stomach and breast cancer. Its poor selectivity, however, limits its therapeutic relevance, resulting in high incidences of bone marrow, gastrointestinal tract and central nervous toxicity.30 Numerous alterations of 5-FU structure have been accomplished to tackle these problems ensuing in the development of 5-FU derivatives viz. floxuridine and tegafur exhibiting better pharmacological and pharmacokinetic properties.31 Molecular conjugate of 5-FU and Camptothecin (CPT), a topoisomerase cytotoxic alkaloid, is another approach to circumvent the problems associated with uracil analogues and have shown to exhibit comparable or superior cytotoxicity to irinotecan (semi-synthetic analogue of CPT and acts via topoisomerase 1 inhibition) with improved selectivity, efficacy and safety.
Recent studies have shown the synthesis of 1H-1,2,3-triazole-tethered isatin-β-lactam conjugates and preliminary analysis of their in vitro activity against T. vaginalis.32 The methodology was further extended to the synthesis of β-amino alcohol tethered isatin-β-lactam as well as piperazine-linked isatin-7-chloroquinoline conjugates, along with their in vitro inhibitory activity against T. vaginalis and Tritrichomonas foetus.33 In continuation of these findings and in view of the reported anti-parasitic potential of uracil, the present study expands the synthesis of mono- and bis-uracil-isatin conjugates as shown in Figure 1 and their in vitro activity against T. vaginalis. The chain length has been meticulously altered so as to carefully analyze the structure–activity relationship among the synthesized hybrids.
Section snippets
Results and discussion
C-5 substituted N-alkylbromo-isatins 2 (Scheme 1) were synthesized via our previously reported protocol involving NaH promoted reaction of isatin with dibromoalkanes at 60 °C. The precursors 2 were purified via column chromatography using 15:85 EtOH/Hexane as eluent and the % age yields of each substituent have been shown in Table 1. The N-alkylated precursors were then employed in the synthesis of desired mono- and bis-uracil-isatin hybrids 4 and 5, respectively as shown in Scheme 2.34 It was
Conclusion
A series of mono- and bis-uracil-isatin conjugates were synthesized and assessed for their in vitro activity against the protozoal pathogen T. vaginalis. SAR studies revealed that the bis-uracil-isatin conjugates viz. 5f, 5k, 5l, 5q and 5r were more effective than their corresponding mono-uracil-isatin counterparts with more than 90% inhibition at 50 μM. The most potent and non-cytotoxic conjugates of this group, 5f and 5m, had an optimum combination of longer alkyl chain length (n = 2 for 5f and,
In vitro protozoal parasite susceptibility assay
Protozoal parasites were cultured for 24 h at 37 °C. To perform the initial susceptibility screens on T. vaginalis, compounds were suspended in DMSO to obtain concentrations of 100 μM; 5 μL aliquots of these suspensions were diluted in 5 mL of TYM diamond’s media to obtain a final concentration of 100 μM. After 24 h, cells were counted using a hemacytometer. Cell counts were normalized to the DMSO controls, in order to allow direct comparison and averaging of the various trials. These data sets were
Acknowledgements
Financial assistance from Department of Science and Technology, New Delhi under Innovation in Science Pursuit for Inspired Research (INSPIRE) Fellowship (K.K.) is gratefully acknowledged. We also thank the Department of Biological Sciences, University of the Pacific, for support of this project.
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