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. Author manuscript; available in PMC: 2019 Apr 1.
Published in final edited form as: Med Chem Res. 2018 Feb 27;27(4):1269–1275. doi: 10.1007/s00044-018-2146-4

Evaluation of Triazole and Isoxazole Derivatives as Potential Anti-infective Agents

Amer H Tarawneh 1,2, Lo′ay A Al-Momani 2, Francisco León 1, Surenda K Jain 1,3, Anastassiya V Gadetskaya 3,4, Sultan T Abu-Orabi 5, Babu L Tekwani 2, Stephen J Cutler 1,6,*
PMCID: PMC6203334  NIHMSID: NIHMS946676  PMID: 30374214

Abstract

A series of isoxazole and triazole derivatives, with interesting bioactive scaffolds, were examined for their in vitro antibacterial, antifungal, and antiprotozoal activities. These compounds exhibited antitrypanosomal activity comparable to difluoromethylornithine (DMFO), a drug used in the treatment of human African trypanosomiasis. Isoxazole analogues 1, 3 and 4, and triazole derivatives 16, 17, 28, 37, 40 and 42 showed the highest antitrypanosomal activity with IC50 values of 17.89, 1.82, 10.38, 10.26, 11.77, 9.29, 3.93, 2.11, and 0.93 μM, respectively. Compounds 40 and 42 showed the most potent activity against Leishmania donovani amastigotes with IC50 values of 18.28 and 10.54 μM, respectively. Compound 42 showed the most potent activity against Leishmania donovani macrophage internalized amastigotes with an IC50 value of 8.32 μM. Conjugate triazoles 40–43 displayed potential antimalarial activity against chloroquine-resistant W2 and chloroquine sensitive D6 Plasmodium falciparum strains (IC50 value range from 0.58 to 8.36 μM). Compound 37 showed antibacterial activity against Staphylococcus aureus, MRSA and Mycobacterium intracellulare with IC50 values of 15.53, 14.22 and 47.45 μM, respectively. None of the compounds exhibited antifungal activity.

Keywords: triazole and isoxazole derivatives, antibacterial and antiprotozoal activity

1. Introduction

Over the last decades, progress on the pharmacological activity and synthesis of various substituted triazole/isoxazole derivatives has been added to the scientific literature. Through this research, compounds containing a triazole-ring have showed a broad spectrum of activities, including anti-inflammatory (Sana et al., 2018), analgesic (Montes et al., 2017), antitumor (Kaur et al., 2016), anti-diabetic (Park and Pham 2017), and anticonvulsive (Chelamalla et al., 2017) activity. Additionally, there are several reports that highlight the importance of the triazoles motif against microbes: bacteria, fungi, protozoa, and virus (Ashok et al., 2018; Cao et al., 2017; Keivanloo et al., 2016; Kumar et al., 2013). In fact, the triazole ring is found on several marketed antifungal drugs including, terconazole, fluconazole, posaconazole, voriconazole and itraconazole (Nett et al., 2016). Similarly, the isoxazole motif is found in several clinically approved antibiotics including oxacillin, cloxacillin, dicloxaciillin and flucloxacillin (Sutherland et al., 1970).

Neglected tropical diseases (NTDs) are disabling and potentially life-threatening infections affecting more than a billion people worldwide (Thao et al., 2014). Human African trypanosomiasis (HAT), commonly known as sleeping sickness, is an NTD caused by the Trypanosoma brucei parasite and transmitted to humans through the bite of the tsetse fly (Tiberti et al., 2013). The parasites can travel through the blood-brain barrier and invade the Central Nervous System (CNS), at which time neurological symptoms begin to appear. In the absence of treatment, the disease results in wasting of body tissue, coma, and ultimately death (Gull 2002). The resulting coma is why this infection is called sleeping sickness. Leishmaniasis is a group of tropical diseases caused by a number of species of protozoan parasites belonging to the genus Leishmania. Cutaneous leishmaniasis and visceral leishmaniasis have been reported to be the two major forms of leishmaniasis in humans (Peixoto et al., 2011). These NTDs are clearly related to poverty since this population of patients does not have access to appropriate medication and healthcare. NTDs have a huge impact on the economic growth in developing countries (Kotowski et al., 2015).

While malaria is not cataloged as a NTD, it is considered the leading cause of death and morbidity worldwide among infectious diseases. It is caused by parasites that are transmitted to people through the bites of female mosquitoes infected with a Plasmodium parasite. There are four main species of the malaria parasite which include P. falciparum, P. malariae, P. vivax and P. ovale. According to the World Health Organization (WHO), in 2016 there were approximately 216 million cases of malaria in 91 countries (WHO 2017). The drugs available for the treatment of these endemic diseases are old, expensive, and associated with other problems including safety. The situation is intensified by the quick development of resistance against therapeutic agents, resulting in drug resistant parasites (WHO 2017).

The control of infectious disease requires continued research on bioactive compounds. In this context, biologically active scaffolds such as heterocyclic compounds possessing triazole and isoxazole derivatives could be used as potential leads. There are few examples of the use of these important heterocyclic motifs against NTDs. Different triazole derivatives showed in vitro and in vivo activity against a variety of strains of T. cruzi and T. brucei brucei. A group of synthesized metal complexes of triazole-pyrimidine derivatives inhibited the in vitro growth of epimastigotes of T. cruzi and procyclic forms of T brucei brucei (Magán et al., 2004). Some isoxazole containing heteroretinoid derivatives showed in vivo antileishmanial activity against Leishmania donovani in hamsters (Suryawanshi et al., 2012). Giannini and Battistuzzi 2015, reported the antiprotozoal activity against T. brucei, T. cruzi and P. falciparum of a series of 3,4,5 isoxazole and 1,4,5 trisubsituted triazole derivatives. These compounds showed nM range activity and excellent binding to the heat shock protein (Hsp90α), confirming the important role that Hsp chaperone proteins play in the live cycle of the parasite. There have been some efforts to conjugate triazole compounds. For example, 3-nitro-1,2,4-triazole with amides and sulfonamides displayed potent T. cruzi activities with IC50 in the nM range (Papadopoulou et al., 2012). Hybrids between 1,2,3-triazole, quinones and sugars showed potential activities against T. cruzi (Jardim et al., 2015).

In continuation of our efforts to find novel active agents against NTDs, a library of triazole and isoxazole compounds were evaluated for their in vitro antitrypanosomal activity, as well as, antileishmanial, antimalarial and antimicrobial properties.

2. Materials and Methods

2.1 Chemistry

The evaluated compounds: twelve isoxazoles 1–12, twenty-four triazoles 13–36 and seven triazole conjugates 37–43 were design and synthesized at the Yarmouk University, Jordan. The general experimental procedure and experimental data for isoxazole and dihydroisoxazole derivatives 1–12 have been reported (Abu-Orabi et al., 1988; Abu-Orabi et al., 1999 and Al-Momani 1995). The synthetic protocols for triazole derivatives 13–36 have been previously described (Abu-Orabi 2002). Compounds 37–39 have been synthesized and their experimental data reported (Tashtuosh et al., 1999). Finally, the synthetic process for compounds 40–43 was previously reported (Abu-Orabi et al., 1988).

2.2 Biological evaluation

2.2.1 In vitro antimicrobial assay

Compounds 1–43 were tested for antimicrobial activity against a panel of microorganisms obtained from the American Type Culture Collection (Manassas, VA, USA) and included the fungi: Candida albicans ATCC 90028, Candida glabrata ATCC 90030, Candida krusei ATCC 6258, Cryptococcus neoformans ATCC 90113, Aspergillus fumigatus ATCC 204305, the bacteria Staphylococcus aureus ATCC 29213, methicillin-resistant S. aureus ATCC 33591 (MRSA), Escherichia coli ATCC 35218, Pseudomonas aeruginosa ATCC 27853, and Mycobacterium intracellulare ATCC 23068. The bioassays were performed as previously described (Ma et al., 2004 and Bharate et al., 2007). Ciprofloxacin and amphotericin B were used as positive drug controls.

2.2.2 In vitro antitrypanosomal assays

Blood stage forms of Trypanosoma brucei brucei was grown in IMDM medium supplemented with 10% fetal bovine serum. The culture was maintained at 37 °C in 5% CO2 incubator. Two day old culture of T. brucei was diluted to 5,000 parasites/ml. Diluted T. brucei parasite culture was dispenses in clear flat bottom culture well plates and treated with test compounds. The antitrypanosomal screening assay was based on Alamar blue based fluorometric growth analysis at concentration range of 10–0.4 μg/ml. Active compounds were further screened at concentration range 10–0.0032 μg/ml. Pentamidine and difluoromethylornithine were used as positive drug controls. IC50 and IC90 values were computed from dose response growth inhibition curve by XLfit version 5.2.2 (Jain et al., 2016).

2.2.3 In vitro antileishmanial assays

Promastigote culture of Leishmanial donovani was grown in RPMI medium with 10% FBS with pH 7.4 at 26 °C. Axenic amastigote culture of Leishmanial donovani was grown in RPMI medium with 10% FBS with pH 5.5 at 37 °C in 5% CO2 incubator. The antileishmanial activity of the compounds was tested in vitro against promastigotes, axenic amastigotes and macrophage internalized amastigote form of Leishmania donovani parasite. Promastigotes and axenic amastigotes assays were based on alamar blue fluorometric growth analysis (Manda et al., 2014). Differentiated THP1 cells were been used in macrophage internalized-amastigote assay. Macrophage internalized amastigote method was based on parasite rescued and transformation assay described earlier, pentamidine and amphotericin B were used as positive standards (Jain et al., 2012).

2.2.4 In vitro antimalarial assays

Antimalarial activity was determined in vitro against chloroquine sensitive (D6, Sierra Leone) and resistant (W2, Indo China) strains of Plasmodium falciparum by a colorimetric assay that determines the parasitic lactate dehydrogenase (pLDH) activity, as described earlier (Hamid et al., 2004).

2.2.5 In vivo antimalarial assays

Plasmodium berghei (NK-65) parasite was obtained from MR4 (Malaria Research Reference Reagents Resource). Male Swiss albino mice weighing ~20 gram were procured from ENVIGO, USA. Animal studies were done under protocol (Protocol approval number 15-007) approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Mississippi, USA. Blood with high parasitemia was collected by cardiac puncture in Acid-Citrate-Dextrose (ACD) solution from these infected mice washed and diluted with sterile saline to adjust the infected RBC’s concentration to 8×107 RBCs/ml. The animals were randomly divided in two different groups with 5 animals in each group and all the mice were inoculated i.p. with 0.5 ml of infected blood for producing the infection. The mice were treated with the test compound oral once daily dose of 11.1 mg/kg from day 0 to 2 post infection. Dose was selected based on maximum tolerated dose of compound 43 in mice.

2.2.6 Cytotoxicity assays

The cultures of Human Acute Monocytic Leukemia Cell Line (THP1 cells) and vero cells were maintained in RPMI medium with 10% FBS in 37 °C 5% CO2 incubator. For the THP1 cytotoxicity assay, four days’ old culture of THP1 cells was diluted with RPMI medium treated with phorbol 12-myristate 13-acetate at 2.5 ng/ml concentration for transformation of the cells to adherent macrophages (Jain et al., 2016). The cytotoxicity assay was done on these differentiated THP1 cells, alamarBlue® cell viability reagent was used to detect fluorometric changes at concentration range of 10–0.4 μg/ml (Jain et al., 2012). Cytotoxicity assay for vero cells was based on the neutral red assay, which was described earlier (Yang et al., 2006).

3. Results and Discussion

A series of twelve isoxazoles 1–12 (Figure 1), twenty-four triazoles 13–36 (Figure 2) and seven triazole conjugates 37–43 (Figure 3) were evaluated for their antibacterial, antifungal, antimalarial antitrypanosomal, antileishmanial and cytotoxicity activities. Out of forty-three tested compounds, twenty-two showed promising antitrypanosomal activity. Four triazole conjugated derivatives (40–43) showed in vitro antimalarial activity. Most of the antitrypanosomal compounds showed comparable activity to the positive control drug difluoromethylornithine (DFMO).

Figure 1.

Figure 1

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Isoxazole and dihydroisoxazole derivatives (1–12)

Figure 2.

Figure 2

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Triazole derivatives (13–36)

Figure 3.

Figure 3

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Triazole conjugated derivatives (37–43)

Antimicrobial activity

The antifungal and antibacterial activities were evaluated against a panel of pathogenic fungi (Candida albicans, C. glabrata, C. krusei, Cryptococcus neoformans, and Aspergillus fumigatus) and a panel of pathogenic bacteria (Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Escherichia coli, Pseudomonas aeruginosa and Mycobacterium intracellulare) associated with opportunistic infections. Only compound 37 possessed antibacterial activity against S. aureus, and MRSA with IC50 values of 15.53 and 14.22 μM, respectively. Compounds 37, 40, 42 and 43 showed significant activity against M. intracellulare with IC50 values of 47.45, 44.83, 43.16 and 7.60 μM, respectively. None of the compounds possessed antifungal activity.

Antitrypanosomal activity

Tables 1–3 show the screening results for antitrypanosomal activity of all compounds. Isoxazole 3 showed the most potent activity against T. brucei with an IC50 value of 1.82 μM (Table 1). Replacing the tertiary butyl ester on the R1 with hydrazinocarbonyl 4 led to reduced activity with a value of 10.38 μM. Changing the methyl group on the benzene ring to methoxy 1, while both R1 and R2 were kept as in 3, did not significantly improve the potency. Modification of the isoxazole in 4 to a 4,5-dihydroisoxazole like in compound 8 lead to lose the biological activity against T. brucei. However, modification replacing the hydrazinocarbonyl R1 with a substituted benzene ring and hydrazinocarbonyl R2 with a benzyl ester in the dihydroisoxazole core yielded compound 10, which showed an IC50 value of 11.51 μM against T. brucei. Replacing the isoxazole moiety of compound 4 with the triazole moiety and keeping the hydrazinocarbonyl in R1 and R2 showed no significant change in the bioactivity against T. brucei. In this series 13–24 halogenated monosubstitution in the aromatic ring showed the highest IC50 values for compounds 15 to 18 (Table 2). Further modification with a trimethyl substitution 22 led to an IC50 value of 22.28 μM. Inserting a bulky group at position R1 and R2 of the triazole ring, such as the pivaloyloxy in compound 34 led the highest potency for this series, with an IC50 value of 7.44 μM. In general, compounds (13–36) containing electronegative groups, such as, halogens showed antitrypanocidal activity. No clear patterns were found to explain the biological effects of the substituents on the benzyl ring.

Table 1.

In vitro antiprotozoal activity of isoxazole (1–7) and dihydroisoxazole (8–12) derivatives

Compound Leishmania donovani macrophage internalized amastigote Trypanosoma brucei
IC50, μM IC90, μM IC50, μM IC90, μM
1 NA NA 17.895 ± 1.079 23.640 ± 0.843
2 NA NA NA NA
3 28.836 ± 0.087 >28.952 1.824 ± 0.086 4.488 ± 0.819
4 NA NA 10.385 ± 3.308 24.792 ± 5.784
5 NA NA NA NA
6 NA NA NA NA
7 NA NA NA NA
8 NA NA NA NA
9 NA NA NA NA
10 NA NA 11.509 ± 2.265 >22.347
11 NA NA NA NA
12 NA NA NA NA
Amp B 0.272 ± 0.100 0.441 ± 0.019 NT NT
DFMO NT NT 21.299 ± 2.013 59.175 ±5.748
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NA: not active; NT: not tested; Amp B = Amphotericin B; DFMO = difluoromethylornithine

Table 3.

In vitro antiprotozoal activity of triazole conjugates (37–43)

Compound L. donovani promastigotes L. donovani Axenic amastigotes L. donovani macrophage internalized amastigote T. brucei P. falciparum
IC50, μM IC90, μM IC50, μM IC90, μM IC50, μM IC90, μM IC50, μM IC9, μM IC50 (D6), μM IC50 (W2), μM
37 NA NA 21.796 ± 0.001 >26.777 23.537 ±2.286 >26.777 3.935 ± 0.079 4.940 ± 0.092 NA NA
38 NA NA NA NA NA NA NA NA NA NA
39 NA NA NA NA NA NA NA NA NA NA
40 14.625 ± 5.757 >22.766 18.281 ± 0.592 22.447 ± 0.016 NA NA 2.117 ± 0.147 6.766 ± 1.918 6.322 ± 0.363 7.611 ± 0.838
41 NA NA NA NA NA NA 4.741 ± 1.735 13.514 ±0.988 8.367 ± 3.041 6.606 ± 0.732
42 16.445 ± 3.868 >21.722 10.536 ± 0.824 18.149 ± 1.651 8.321 ± 0.327 12.879 ±5.811 0.926 ± 0.034 1.200 ± 0.026 1.909 ± 0.403 2.886 ± 0.701
43 NA NA NA NA NA NA 7.595 ± 2.119 10.468 ± 3.234 0.697 ± 0.187 0.583 ± 0.140
Amp B 0.192 0.312 1.729 2.004 0.272 ± 0.100 0.441 ±0.019 NT NT NT NT
Pent 2.036 3.668 15.345 16.872 6.531 >16.872 NT NT NT NT
DFMO NT NT NT NT NT NT 21.299 ±2.013 59.175 ±5.748 NT NT
CQ NT NT NT NT NT NT NT NT 0.052 0.46
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NA: not active; NT: not tested; Amp B = Amphotericin B; Pent = pentamidine; DFMO = difluoromethylornithine; CQ = chloroquine

Table 2.

In vitro antiprotozoal activity of triazole derivatives (13–36)

Compound T. brucei
IC50, μM IC90, μM
13 18.277 ± 4.703 27.023 ± 0.523
14 22.279 ± 5.081 32.159 ± 0.653
15 18.340 ± 6.856 28.058 ± 1.866
16 10.268 ± 0.396 21.665 ± 1.312
17 11.774 ± 1.997 24.452 ± 0.095
18 14.174 ± 9.934 >28.235
19 25.813 ± 5.853 >34.099
20 NA NA
21 NA NA
22 22.278 ± 6.227 >31.511
23 NA NA
24 NA NA
25 NA NA
26 NA NA
27 NA NA
28 9.293 ± 3.071 17.689 ± 7.967
29 NA NA
30 NA NA
31 NA NA
32 41.026 ± 1.059 >42.514
33 32.838 ± 0.892 >34.100
34 7.445 ± 1.209 9.486 ± 1.436
35 40.218 ± 1.615 >42.514
36 NA NA
DFMO 21.299 ± 2.013 59.175 ±5.748
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NA: not active; NT: not tested; DFMO = difluoromethylornithine

In the series of conjugate triazole-oxadiazole compounds (37–39), compound 37 showed the highest activity with an IC50 value of 3.93 μM. The quinone-triazole conjugate compounds (40–43) showed in overall the highest bioactive potency for all the series against T. brucei with IC50 values of 2.12, 4.74, 0.93, and 7.60 μM, respectively (Table 3). Compound 42 has a strong deactivating substituent and was the most potent against T. brucei. Cytotoxicity screening was done for all tested compounds. None of the compounds showed more than 50 % inhibition on differentiated THP1 cells with the exception of compound 42 with an IC50 value of 10.10 μM.

Antileishmania activity

Antileishmania activity data is shown for active compounds in Tables 1 and 3. For isoxazoles derivatives and triazoles conjugates, analogues 37, 40, and 42 exhibited the highest inhibition values for L. donovani axenic amastigote with IC50 value of 21.80, 18.28 and 10.54 μM, respectively. Analogues 37 and 42 have high activity on the macrophage internalized amastigote form of Leishmania donovani parasite with IC50 values of 23.54 and 8.32 μM, respectively.

Antimalarial activity

All compounds 1–43 were tested against P. falciparum D6 and W2 strains. Activity was found only for compounds 40–43. These compounds showed promising action against both chloroquine-resistant (P. falciparum W2) and chloroquine-sensitive strains of malaria (P. falciparum D6) (Table 3). Compound 43 showed the most potent activity with IC50 values of 0.70 and 0.59 μM, for D6 and W2, respectively. Replacing the 3-fluoro substitution with chloro 40, methyl 41, or nitro 42 groups reduced the activity of this series. All the compounds were evaluated for cytotoxicity against mammalian kidney cell line (Vero) and selectivity index was calculated. Selectivity index values less than 1.2 indicated that antimalarial activity was not due to cytotoxicity. Antimalarial activity of compound 43, the most potent of all the series was tested in vivo in P. berghei mouse malaria model for survival (Figure 4). Chloroquine served as the positive control. Compound 43 increased the survival time to 16.2 days when compared to the vehicle control group of mice at a dose of 11.1 mg/kg per day for 3 days.

Figure 4.

Figure 4

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Survival chart for mice in antimalarial study (43)

In conclusion, we report the antimalarial, antileishmanial, antibacterial activities of 43 isoxazole and triazole derivatives. Triazole compounds 13–36 were active against T. brucei, while compound 37, having triazole and oxadiazole rings, showed promising activities against all pathogens. Compounds 40–43 produced the most potent antileishmanial and antimalarial activities. Further explorations of these triazole derivatives can provide lead compounds for antimicrobial agents.

Supplementary Material

44_2018_2146_MOESM1_ESM

Acknowledgments

The authors thank Dr. Shabana Khan for performing the antimalarial assays. The work was supported by grant number P20GM104932 from the National Institute of General Medical Sciences (NIGMS), a component of the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIGMS or the NIH. Furthermore, this investigation was conducted in a facility constructed with support from research facilities improvement program C06RR14503 from the NIH National Center for Research Resources (NCRR).

Footnotes

Conflict of Interest: The authors declare that they have no conflict of interest.

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