Preliminary communicationSynthesis of 1H-1,2,3-triazole linked β-lactam–isatin bi-functional hybrids and preliminary analysis of in vitro activity against the protozoal parasite Trichomonas vaginalis
Graphical abstract
Synthesis of 1H-1,2,3-triazole-tethered β-lactam–isatin structural chimeras and their in vitro activity against Trichomonas vaginalis at 10 and 100 μM.
Highlights
► Synthesis of 1H-1,2,3-triazole-tethered β-lactam–isatin structural chimeras. ► In vitro activity was evaluated against T. vaginalis at 10 and 100 μM. ► The compound 5i proved to be non-cytotoxic with an IC50 of 7.69 μM.
Introduction
Parasitic infections represent a major health threat in under-developed countries, and have a deep impact on public health. Malaria has been a major source of parasitic infections since antiquity, yet today it remains responsible for the deaths of more than one million people every year [1]. Similarly, infections such as Trypanosoma cruzi, Leishmania mexicana, Giardia lamblia, Entamoeba histolytica and Trichomonas vaginalis have worldwide distribution, especially in under-developed countries where tropical climates prevail in combination with poor sanitation and hygiene [2], [3], [4]. T. vaginalis, the causative organism of trichomoniasis is a mucosal pathogen which affects the human urogenital tract, producing malodorous vaginal discharge, vulval irritation and inflammation, and punctate cervical microhemorrhages [5]. It is now well established that trichomoniasis, significantly increase the host's vulnerability to contract HIV [6], [7] and controlling it could significantly reduce the transmission of new HIV infections. Although the introduction of metronidazole heralded a new era for the treatment of parasitic infections [8], the recent revelations of its toxic effects, including genotoxicity, gastric mucus irritation [9], [10], and the development of clinical resistance [11] demonstrate the need for the development of new and efficient scaffolds against trichomoniasis.
The isatin (1H-indole-2,3-dione) moiety is a versatile scaffold with wide possibilities for chemical modification, and is responsible for a broad spectrum of biological properties in many synthetically versatile molecules [12]. In recent years, Schiff and Mannich bases of 1H-indole-2,3-diones were reported to exhibit chemotherapeutic properties including antiviral [13], antitubercular [14], antifungal, and antibacterial activities [15]. Investigation of the SARs in 1H-indole-2,3-dione derivatives revealed that 5-halogenation [14], [15], N-alkylation [16], N-Mannich base [15], and 3-thiosemicarbazone formation were effective in triggering a marked rise in activity against various bacteria, fungi, and viruses. Moreover, cyclization of 1H-indole-2,3-diones to 4-thiazoline [14], 4-thiazolidinone [17], and pyridazinoindole [16] was efficient in increasing anti-microbial activity. Previous studies have also reported the inhibitory activity of isatin–β-thiosemicarbazones and isatin derivatives on HIV replication [18], which has been extended towards the synthesis of diverse N-Mannich base derivatives of 5-substituted isatins with potential non-nucleoside reverse transcriptase inhibitor (NNRTI) activity.
β-Lactam nucleus is an important heterocyclic core with pronounced biological activities and present in most widely used antibiotics such as penicillins [19], cephalosporins [20], carbapenems and monobactams [21], [22]. In recent years, synthesis and modification of the β-lactam ring to obtain compounds with diverse pharmacological activities such as cholesterol absorption inhibitors, human cytomegalovirus protease inhibitors, thrombin inhibitors, anti-hyperglycaemic, anti-tumour, anti-HIV, anti-inflammatory, analgesic activities and serine-dependent enzyme inhibitors has generated a renewed interest for this class of anti-microbial agents [23].
In continuation of our pursuit of the synthesis of biologically potent novel functional entities [24], we present herein the synthesis of 1H-1,2,3-triazole tethered bi-functional hybrids of C-5 substituted isatins with N-1 substituted β-lactams (Fig. 1) and their in vitro evaluation against T. vaginalis. The introduction of 1H-1,2,3-triazole as linker is based on its ability to confer favourable properties viz. moderate dipole character, hydrogen bonding capability, rigidity and stability under in vivo conditions on the synthesized hybrids [25].
Section snippets
Synthetic chemistry
The desired bi-functional hybrids were synthesized using click chemistry approach between N-substituted β-lactams and 5-substituted isatins containing the azide and terminal alkyne respectively, in the presence of Cu(I) catalyst. The 5-substituted isatins were prepared according to reported procedures and N-propargylation was done using propargyl bromide in the presence of NaH as a base, and DMF as solvent (Scheme 1, Scheme 2, Scheme 3). The desired N-substituted 3-azido-β-lactams 4 were
Experimental section
Melting points were determined by open capillary using Veego Precision Digital Melting Point apparatus (MP-D) and are uncorrected. 1H NMR spectra were recorded in deuterochloroform and DMSO-d6 with Jeol 300 (300 MHz) spectrometers using TMS as internal standard. Chemical shift values are expressed as parts per million downfield from TMS and J values are in hertz. Splitting patterns are indicated as s: singlet, d: doublet, t: triplet, m: multiplet, dd: double doublet, ddd: doublet of a doublet
Acknowledgements
Financial assistance from Board of Research in Nuclear Sciences under DAE Research Award for Young Scientist Scheme (VK) is gratefully acknowledged.
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Recent developments in anti-Trichomonas research: An update review
2018, European Journal of Medicinal ChemistryCitation Excerpt :Vipan Kumar and coworkers have synthesized eighteen compounds as 1H-1,2,3-triazole linked β-lactam-isatin bi-functional hybrids by copper-catalyzed ‘click chemistry and performed bioactivity against G3 strain of T. vaginalis. Compound 21 with phenyl-substituent on N-1 of β-lactam ring and unsubstituted isatin ring was found to be the most active showing IC50 of 7.69 μM along with non-cytotoxic behaviour [27]. They further synthesized mono and bis-uracil isatin conjugates and evaluated against T. vaginalis at 50 μM.
4-Aminoquinoline-ferrocenyl-chalcone conjugates: Synthesis and anti-plasmodial evaluation
2017, European Journal of Medicinal ChemistryRecent Progress in the Use of Functionalized β-Lactams as Building Blocks in Heterocyclic Chemistry
2016, Progress in Heterocyclic ChemistryCitation Excerpt :A selection of the newly synthesized hybrid structures has been evaluated for their antiviral activity, cytotoxicity, and cytostatic activity, revealing a significant cytostatic effect of one of the derivatives against L1210 (murine leukemia) and CEM (human T-lymphocyte) tumor cells (14S2436). Other examples of biologically active β-lactam chimeras include saccharide-β-lactam hybrids (lectin inhibition) (08OL2227), 7-chloroquinoline-β-lactam hybrids (antimalarial activity) (12BMCL57, 14EJM(71)128), chalcone-β-lactam hybrids (e.g., hybrid 110, anticancer activity) (12EJM(47)594), isatin-β-lactam hybrids (activity against the protozoal parasite Trichomonas vaginalis) (13EJM(63)897, 14MI3671), retinoid-β-lactam hybrids (differentiative effects) (13EJM(70)857), combretastatin-β-lactam hybrids (treatment of combretastatin-resistant carcinomas) (13MI2451), and 4-aminoquinoline-β-lactam hybrids (e.g., hybrid 111, antimalarial and antitubercular activity) (14MI191). Finally, the synthesis of N-[4-(2-oxoazetidin-1-yl)-but-1-enyl]acetamides 115 can be mentioned, which can be seen as medicinally interesting enamide-β-lactam hybrids.