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Antileshmanial Activities of Synthetic Substituted 2-phenyl-4-[phenylmethylidene]-1,3-oxazol-5(4H)-ones.

Byline: Saadia Razi Khan, Nida Ghouri, Aneela Karim, Farzana Naz, Muhammad Imran Fakhri Shahnaz Perveen, Khalid Mohammed Khan and Muhammad Iqbal Choudhary

Summary: Substituted 2-phenyl-4-[phenylmethylidene]-1,3-oxazol-5(4H)-ones 1-27 were evaluated for their activity against Leishmania major. Compounds 1-27 demonstrated in vitro antileishmanial activities with IC50 values between 28.9 - 69.05 M, as compared to standard drug pentamidine (IC50 = 5.09 0.04 M). Compounds 12 (IC50 = 28.90 1.10 M), 24 (IC50 = 31.4 2.15 M), 13 (IC50 = 35.0 3.18 M), 16 (IC50 = 35.0 3.13 M), and 25 (IC50 = 35.0 3.18 M) displayed signifiant antileishmanial activities. Whereas, compounds 8-10, 15, 19, and 26 with IC50 values of 62.2 3.36, 57.8 2.30, 57.72 5.02, 56.18 4.40, 57.85 2.25, 69.05 6.20, 54.8 1.50, and 57.8 2.30 M showed a moderate antileishmanial activities.

Keyword: Substituted 2-phenyl-4-[phenylmethylidene]-1,3-oxazol-5(4H)-one, Antileishmail activities.

Introduction

Leishmaniasis, is a widespread parasitic disease, endemic to the American, African and Asian tropical countries, produced by Leishmania species. These parasites provoke multiple granulomatose or diffuse, auto-inoculable and even metastatic skin ulcers, resembling leprosy lesions. It affects some 12 million people around the world [1]. The disease is reported from various areas of Pakistan especially Balochistan and the upper Sindh have high incidents of cutaneous leishmaniasis [2].

Pentavalent antimonials sodium stibogluconate and meglumineantimoniate are being use as antileishmanial therapy, despite the fact that they are toxic for kidney and heart. In addition, drugs such as amphotericin B, pentamidine, and other nitrogen-derivatives also cause diverse side effects. These drugs present high toxicity and require intravenous therapy. Additionally, recently pentavalent antimonial resistant is developed, especially in cases of Leishmania/HIV co-infection. Therefore new therapeutic agents with better results and low toxicity are still needed [3].

2-Alkylquinolines and 2-arylquinolines, isolated from plants source are drug candidates, as they exhibit antiprotozoal activity (e.g. against Leishmania sp. Plasmodium, Trypanosoma sp. and Trichomonas vaginalis), and inhibit the human immunodeficiency virus of type-1 (HIV-1) integrase as well as the proliferation of HTLV-1 transformed cell lines (HUT-102) [4].

Oxazolones are heterocyclic compounds used in the synthesis of several organic molecules, including amino acids, antimicrobials, antitumors compounds, immunomodulators, and heterocyclic precursors for biosensors coupling, photosensitive composition devices, amino alcohols, thiamine, amides, peptides, and polyfunctional compounds [5]. 5(4H)-Oxazolones are known for their use in the synthesis of a number of important heterocyclic compounds. These compounds are also used as versatile reagents for the synthesis of keto and arylacetic acids [6].

Several methods are available for the synthesis of oxazolones including the use of acetic anhydride, sodium acetate, lead acetate, polyphosphoric acid, sulfur trioxide/dimethyl formamide complex, perchloric acid, and carbodiimides. Recently, synthesis of oxazolones has been reported by using anhydrous zinc chloride or bismuth (III) acetate as catalysts [7].

In the course of our research work focused on the synthesis of diverse heterocycles [8, 9], we synthesize new derivatives of 4-substituted arylidene2-phenyl oxazolones 1-27 and their antileishmanial activity against the promastigote form of Leishmania donovani was evaluated in our drug designing and discovery program [10-14].

Experimental

All chemicals, reagents, and solvents were purchased from Merck (Germany), TCI (Tokyo Chemical Industries, Tokyo, Japan) and Sigma- Aldrich (Germany). The purity of synthesized compounds was confirmed by Thin-layer chromatography using 30% ethyl acetate in n-hexane. ALUGRAM silica gel 60 F254 (MACHEREYNAGEL GmbH and Co. KG, DA1/4ren, Germany) was used for TLC analysis. The melting points were determined on a Stuart SMP40 melting point apparatus (Staffordshire, United Kingdom) and were uncorrected. H1 NMR (300 MHz, DMSO) were recorded on a Bruker 300 spectrometer and the UV and IR spectra were recorded on Evolution 300 (Thermo Scientific) and FTIR-8900 (Shimadzu, Japan) spectrophotometers, respectively. The mass spectra were recorded on JEOL MS Route, JEOL JMS 600-H, MAT 312 spectrometers. Elemental analysis was carried out on Series II CHN-O-rapid analyzer 2400 (Perkin Elmer, USA).

Table-1: Antileishmanial activities of compounds 1-27.

Compound###R###IC50 SEM(g/mL)a Compound###R###IC50 SEM(g/mL)a

###1###NAb###15###69.0 6.20

###2###NAb###16###35.0 3.18

###3###NAb###17###NAb

###4###NAb###18###NAb

###5###62.2 3.36###19###54.8 1.50

###6###NAb###20###NAb

###7###57.8 2.30###21###NAb

###8###57.7 5.02###22###NAb

###9###56.1 4.40###23###NAb

###10###57.8 2.25###24###31.4 2.15

###11###NAb###25###35.0 3.18

###12###28.9 1.1###26###57.8 2.30

###13###35.0 3.18###27###NAb

###14###NAb###28###5.09 0.09

In Vitro Leishmanicidal Assay

Leishmania major promastigotes were grown in bulk early in modified NNN biphasic medium using normal physiological saline. Leishmania parasite promastigotes were cultured with RPMI 1640 medium (Sigma, St. Louis, USA) supplemented with 10% heat inactivated fetal Calf serum (FCS) (PAA Laboratories GmbH, Austria). Parasites at log phase were centrifuged at 2000 rpm for 10 minutes, and washed three times with saline at same speed and time. Parasites were diluted with fresh culture medium to a final density of 1X 106 cells/mL.

In a 96-well micro-titer plate, medium was added in different wells; 20 L of the tested compound was added in medium and serially diluted. 100 L of parasite culture was added in all wells. Two rows were left for negative and positive control. Negative controls received only medium while the positive control contained varying concentrations of standard antileishmanial compound pentamidine (ICN Biomedical Inc, USA). The plates were incubated between 22-25 C for 72 h. The culture was examined microscopically on an improved Neubaure counting chamber and IC50 values of fractions possessing antileishmanial activity were calculated by Software Ezfit 5.03 Perella Scientific, USA. All assays were run in triplicates [15-17].

Scheme-1: Synthetic route for the compounds 1-27

General Procedure for the Syntheses of Compounds 1-27

A mixture of substituted aldehyde (5.0 mmol), N-benzoylglycine (5.0 mmol), acetic anhydride (5.0 mL, 56.0 mmol), freshly fused sodium acetate (1.0 g, 12.1 mmol) in a round-bottomed flask was heated on steam bath, after liquefaction, heating was continued for additional 2 h. After the completion of reaction (TLC analysis), mixture was left for cooling. Solid was separated out upon cooling, was filtered and washed with acetic acid and water. Crystallization from ethanol afforded compounds 1-27. The structures of all the synthesized compounds were elucidated using different spectroscopic techniques such as 1H-NMR, EI-MS, UV, and IR.

Results and Discussion

Chemistry

Oxazolones derivatives 1-27 were synthesized by following Erlenmeyer-Polchl method [18], from appropriate aldehyde and hippuric acid via cyclodehydration condensation in dry acetic anhydride in the presence of anhydrous sodium acetate (Scheme 1) [19]. Completion of the reaction was monitored by TLC analysis. The structures of the synthesized compounds were elucidated using different spectroscopic techniques such as 1H-NMR, EI-MS, UV, and IR.

In vitro Anti-leishmanial Activities of the compounds 127

Substituted 2-phenyl-4-[phenylmethylidene]1,3-oxazol-5(4H)-ones 1-27 were evaluated for their activity against Leishmania major promastigotes and results are shown in Table-1.

Compounds 1-27 demonstrated a varying degree of in vitro antileishmanial activities with IC50 values ranging between 28.9 1.10 - 69.05 6.20 M, and compared with standard drug pentamidine (IC50 = 5.09 0.04 M). Compounds 12 (IC50 = 28.90 1.10 M), 24 (IC50 = 31.4 2.15 M), 13 (IC50 = 35 3.18 M), 16 (IC50 = 35 3.13 M), and 25 (IC50 = 35 3.18 M) were found to be the most active analogs with significant antileishmanial activities. However, compounds 5, 7, 8, 9, 10, 15, 19, and 26 with IC50 values of 62.2 3.36, 57.8 2.30, 57.72 5.02, 56.18 4.40, 57.85 2.25, 69.05 6.20, 54.8 1.50, and 57.8 2.30 M were found moderately active. All other compounds showed less than 50% inhibition.

Limited SAR suggested that the antileishmanial activities of this series of compounds depend upon the nature and types of substituent groups attached to the 1,3-oxazolone moiety. Compound 12 (IC50 = 28.90 1.10 M) found to be active most compound of the series, possesses bromine and methoxy group at positions 3 and 4 of the phenyl ring, respectively, showing bromine and methoxy residues at phenyl ring are responsible for antileihmanial activity.

In contrary, compound 18 showed no activity although it has two bromine residues at positions 3 and 5, respectively, along with an acetoxy residue at position 4. This activity differences may be due an extra bromine or presence of an acetoxy group at position 3 or absence of methoxy residue at position 4. Difference in activities of compounds 7 (IC50 = 57.8 2.30 M), 22 (inactive), may be due the same reason, although, both have bromine residues at position 3 along with other substituent at different position. Compound 24 (IC50 = 31.4 2.15 M) having a tert-butyl group at position 4 showed second highest activity. In comparison, compound 21 has two tert-butyl substituent at positions 3 and 5 along with a hydroxy at position 2 found to be inactive.

The reason of this inactivity probably is due positional difference of tert- butyl group or presence of an extra tert-butyl residue and hydroxyl substitution at position 2. Amazingly, 13 (IC50 = 35.0 3.18 M), 16 (IC50 = 35.0 3.18 M), and 25 (IC50 = 35.0 3.18 M) showed comparable degree of antileishmanial activity. Compound 13 (IC50 = 35.0 3.18 M) containing 2,4-dichloro groups, compound 16 (IC50 = 35.0 3.18 M) has 2,4-dimethyl groups, and compound 25 (IC50 = 35.0 3.18 M) bearings 3-acetoxy and 4-methoxy substitutions. The activities of these compounds indicating that suitable substituent at the appropriate positions of the phenyl ring are responsible for altering antileishmanial activities.

Acknowledgements

The authors are thankful to the Higher Education Commission (HEC), Pakistan, for financial supports under National Research Program for University (Project No. 20-2073).

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