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Synthesis of 2-(6-substituted quinolin-4-yl)-1-(4-aryl-1H-1,2,3-triazol-1- yl) propan-2-ol as potential antifungal and antitubercular agents
Article in European Journal of Medicinal Chemistry Reports · April 2023
DOI: 10.1016/j.ejmcr.2023.100102
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Synthesis of 2-(6-substituted quinolin-4-yl)-1-(4-aryl-1H-1,2,3-triazol-1-yl) propan-2-ol as potential antifungal and antitubercular agents
Abhijit Shinde
a, Prashant P. Thakare
a, Yogesh Nandurkar
a,b, Manish Bhoye
a,c, Abhijit Chavan
a, Pravin C. Mhaske
a,*aPost-Graduate Department of Chemistry, S. P. Mandali's Sir Parashurambhau College, (Affiliated to Savitribai Phule Pune University), Tilak Road, Pune, 411 030, India
bDepartment of Chemistry, N. Wadia College, (Affiliated to Savitribai Phule Pune University), Pune, India
cDepartment of Chemistry S. N. Arts, D. J. M. Commerce, And S. N. S. Science College, (Affiliated to Savitribai Phule Pune University), Sangamner, India
A R T I C L E I N F O Keywords:
Quinoline 1,2,3-Triazole Antitubercular activity Antifungal activity
A B S T R A C T
The intense pressure of resistance to antibiotics leads the whole world's health security to drastic conditions due to Mycobacterial and fungal infections. To search for potent antifungal and antitubercular lead compounds, the synthesis of a new series of 2-(6-substituted quinolin-4-yl)-1-(4-aryl-1H-1,2,3-triazol-1-yl)propan-2-ol, (9a-l) de- rivatives by click reaction of 1-azido-2-(quinolin-4-yl)propan-2-ol, (7a-d) and substituted ethynylbenzene (8a-c) is reported. The structures of the novel synthesized 2-(6-substituted quinolin-4-yl)-1-(4-aryl-1H-1,2,3-triazol-1-yl) propan-2-ol derivatives were characterized by1H NMR,13C NMR spectroscopic and Mass spectrometric analysis.
The synthesized compounds were examined for antifungal activity againstC. albicans(NCIM 3100),A. niger (ATCC 504) and antitubercular activity againstMycobacterium tuberculosisH37Rv (MTB) (ATCC 25177). Eleven derivatives showed good to excellent antifungal activity againstA. nigerwith MIC 7.81–62.5μg/mL. To study the plausible antifungal mode of action, compounds9e,9f,9g,9i, and9kwere further evaluated for the ergosterol biosynthesis inhibition activity. All these compounds showed ergosterol biosynthesis inhibition activity. All twelve derivatives of 2-(6-substituted quinolin-4-yl)-1-(4-aryl-1H-1,2,3-triazol-1-yl)propan-2-ol, (9a-l) showcased excellent antitubercular activity againstM. tuberculosisH37Rv with MIC 1.6–3.2μg/mL. No significant cytotoxic activity was displayed by these novel derivatives against l929 mousefibroblast cells. The potential antifungal and antitubercular activities compelled the conclusion that the 2-(6-substituted quinolin-4-yl)-1-(4-aryl-1H-1,2,3-tri- azol-1-yl)propan-2-ol derivatives could assist in the development of lead compounds for the treatment of tuberculosis and fungal infections.
1. Introduction
After COVID-19, the foremost cause of mortality from a single in- fectious agent is Tuberculosis (TB), an infection caused byMycobacterium tuberculosis(MTB) developed a threat to global health security. As per the TB report of the World Health Organization (WHO) 2021, 10 million people developed TB in 2020 and 1.5 million died [1]. Over the years, the extensive advent of drug resistance in the causative pathogen, MTB, has been a hurdle to global commitments, to end TB [2,3]. The current treatment regimens for TB disease rely on a combination of drugs (isoniazid, rifampicin, ethambutol, and pyrazinamide). Unfortunately, the appearance of drug resistance is associated with suboptimal efficacy, toxicity, long duration, and poor adherence to these drugs [4–7].
Multidrug-resistant (MDR) or widely drug-resistant (XDR) TB therapy
includes much more toxic and expensive drugs and is tainted by a diminished chance of success [8,9]. Fungal infections are one of the leading causes of hospital-acquired infections [10,11]. The existing antifungal drugsflucytosine and azoles are becoming ineffective due to the emergence of resistant strains and drugs such as amphotericin B are toxic [12,13]. This drives us to an urgent need for the development of effective new anti-TB and antifungal drugs with better efficacy, reduced duration of action, along with improved patient compliance.
Quinoline pharmacophores containing natural and synthetic com- pounds (Fig. 1) fulfilled the medicinal need of society for the lastfive decades. The quinoline analogs have an immense impact on biological activity [14,15]. Many quinoline derivatives have been successfully marketed as antimycobacterial, antimalarial, and anticancer agents. The quinoline and quinolone compounds have a strong capability for the
* Corresponding author.
E-mail address:[email protected](P.C. Mhaske).
H O S T E D BY Contents lists available atScienceDirect
European Journal of Medicinal Chemistry Reports
journal homepage:www.editorialmanager.com/ejmcr/default.aspx
https://doi.org/10.1016/j.ejmcr.2023.100102
Received 5 October 2022; Received in revised form 15 January 2023; Accepted 23 January 2023 Available online 30 January 2023
2772-4174/©2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
European Journal of Medicinal Chemistry Reports 7 (2023) 100102
broad spectrum of biological activities such as antituberculosis [16,17], antimicrobial [18,19], anticancer [20], antimalarial [21,22], anti-inflammatory [23] and antiviral [24] activities.
For the last two decades, triazoles received more attention due to a vital part of numerous bioactive molecules [25,26]. They are one of the key pharmacophores of several antifungal drugs [27,28] and still keep the leading and progressive position in antifungal drug research and development (Fig. 2). 1,2,3-Triazole derivatives are known to exhibit a wide spectrum of pharmacological activities such as antitubercular [29–31], antifungal [32,33], antimicrobial [34,35], antimalarial [36], antivirals [37], anticancer [38,39], antitumor [40], anticonvulsant [41], anti-inflammatory [42], antiplasmodial [43], Store-Operated Calcium Entry inhibitors [44], neuroprotectants for Alzheimer's disease [45], β-Lactamase inhibitors [46], and anti-leishmanial activities [47].
Quinolines clubbed with azoles were reported for promising antitu- bercular activity [48–50] and quinoline-appended triazoles showed potent antitubercular and anti-fungal activity [51]. Owing to the bio- logical significance of quinoline and 1,2,3-triazole derivatives and the search for new anti-infective lead compounds, we report herein the synthesis of 2-(6-substituted quinolin-4-yl)-1-(4-aryl-1H-1,2,3-tri- azol-1-yl)propan-2-ol as potential antitubercular and antifungal agents.
2. Results and discussion 2.1. Chemistry
The synthesis of 1-(6-substituted quinolin-4-yl)ethanone (5a-d) and 2-(6-substituted quinolin-4-yl)-1-(4-aryl-1H-1,2,3-triazol-1-yl)propan-2- ol, (9a-l) derivatives is depicted inSchemes 1 and 2, respectively. The reaction of pyruvic acid and 5-substituted isatin in the aqueous potassium hydroxide at 60 C gave quinoline-2,4-dicarboxylic acids (2a). The
selective mono decarboxylation of dicarboxylic acid (2a) was achieved at 210C in nitrobenzene gave 4-quinoline carboxylic acid (3a). Acids (3a) were coupled with DMHA⋅HCl using EDC⋅HCl as a coupling reagent and DMAP as a base in DCM gaveN-methoxy-N-methylquinoline-4-carbox- amide (4a). Carboxamide (4a) on reaction with MeMgBr gave 1-(qui- nolin-4-yl)ethenone (5a).
The 1-(quinolin-4-yl)ethanone, (5a) on epoxidation reaction with trimethylsulfonium iodide and KOH in DMSO gave 4-(2-methyloxiran-2- yl)quinoline (6a). Sodium azide as a nucleophile was added to 4-(2- methyloxiran-2-yl)quinoline (6a) in ethanol and produced 1-azido-2- (quinolin-4-yl)propan-2-ol, (7a).The click reaction of ethynylbenzene (8a) and 1-azido-2-(quinolin-4-yl)propan-2-ol, (7a) with catalytic copper sulfate and sodium ascorbate in DMF:H2O (2:1) furnished 1-(4-phenyl- 1H-1,2,3-triazol-1-yl)-2-(quinolin-4-yl)propan-2-ol, (9a). Synthesis of 2- (6-substituted quinolin-4-yl)-1-(4-aryl-1H-1,2,3-triazol-1-yl)propan-2-ol, (9b-l) derivatives was achieved using similar reaction conditions. The structure of all synthesized quinolinyl-1,2,3-triazolyl-propan-2-ol de- rivatives was confirmed using spectral analysis. All the derivatives were evaluated for antitubercular and antifungal activity.
1H NMR spectrum analysis of compound 2-(6-bromoquinolin-4-yl)-1- (4-phenyl-1H-1,2,3-triazol-1-yl)propan-2-ol, (9d) revealed a singlet atδ 1.76 integrated for three protons assigned to methyl protons. Two dou- blets atδ4.92 and 5.00 integrated for one proton each were assigned to diastereotopic protons of the methylene (N–CH2–C) group. A singlet atδ 6.44 integrated for one proton was assigned to the C–OH group. Thefive protons of the phenyl ring resonated as two triplets atδ7.37 (integrated for one proton) and 7.48 (integrated for two protons) and a doublet atδ 7.87 (integrated for two protons). A singlet atδ8.45 integrated for one proton was assigned to the C-5 proton of the 1,2,3-triazole ring. The four doublets resonated atδ7.63, 8.05, 8.91, and 9.13 assigned to C-2, C-8, C- 1, and C-5, protons of the quinoline ring, respectively. A double doublet Fig. 1.TB-drugs and lead molecules containing quinoline pharmacophore.
Fig. 2.Antifungal drugs and lead compounds containing Triazolyl-alcohol.
A. Shinde et al. European Journal of Medicinal Chemistry Reports 7 (2023) 100102
2
atδ7.92 integrated for one proton was assigned to the C-7 proton of the quinoline ring. The13C NMR spectrum of compound9dshowed three signals in the aliphatic region atδ27.49, 59.70, and 74.76, assigned to methyl, methylene, and quaternary carbons, respectively. The aromatic carbons of quinoline, phenyl and 1,2,3-triazole rings resonated betweenδ 150.94–119.78. The structure of compound9dwas further confirmed by molecular ion peaks (HRMS) atm/z¼569.1536 (MþH)þ, 571.1507 (Mþ2þH)þ.
2.2. Antifungal activity
Synthesized 2-(6-substituted quinolin-4-yl)-1-(4-aryl-1H-1,2,3-tri- azol-1-yl)propan-2-ol, (9a-l) derivatives were assessed forin vitroanti- fungal activity againstC. albicans (NCIM 3100),A. niger(ATCC 504) using the well diffusion method [52,53]. Ravuconazole and Fluconazole antifungal drugs were used as references. All the test solutions were prepared in DMSO at 500μg/mL concentrations and the wells werefilled with 80μL (40μg) of the samples. The result of antimicrobial activity in the zone of inhibition (mm) is presented inTable S1.
The preliminary antifungal activity results revealed that, except compound9l, all compounds reported good to excellent antifungal ac- tivity against A. niger and moderate activity against C. albicans. The convincing antimicrobial activity of compounds (9a-l) encouraged us to explore microbial inhibition in a dose-dependent way. All the derivatives (9a-l) were further evaluated for minimum inhibitory concentration (MIC) ranging from 250 to 3.90 μg/mL. The in vitro antimicrobial screening results of MIC inμg/mL are presented inTable 1.
The antifungal activity analysis presented inTable 1Provided some lead molecules that showed good antifungal activity againstA. niger. The structure-activity relationship revealed that amongst the 2-(quinolin-4- yl)-1-(4-aryl-1H-1,2,3-triazol-1-yl)propan-2-ol (9a-c), compound9a(R
¼H, R1¼H) and9b(R¼H, R1¼CH3) presented good activity against
A. nigerwith MIC 62.5μg/mL which was twofold less with respect to the standard drug Ravuconazole. AgainstA. niger, the compound (9c) (R¼H, R1¼OCH3) showed comparable activity with respect to the standard drug Ravuconazole with MIC 31.25μg/mL.
From the compounds, 2-(6-bromoquinolin-4-yl)-1-(4-aryl-1H-1,2,3- triazol-1-yl)propan-2-ol (9d-f), compounds (9d) (R¼Br, R1¼H) and (9f) (R¼Br, R1¼OCH3) reported comparable activity againstA. niger with MIC 31.25μg/mL whereas compound (9e) (R¼Br, R1¼ CH3) showed excellent activity againstA. nigerwith MIC 15.62μg/mL which is twofold more active than Ravuconazole and two-fold less active than the Fluconazole. Among the compounds 2-(6-chloroquinolin-4-yl)-1-(4-aryl- 1H-1,2,3-triazol-1-yl)propan-2-ol (9g-i), the compounds9g(R¼Cl, R1
¼H) and9h(R¼Cl, R1¼CH3) showed excellent activity againstA. niger with MIC 15.62μg/mL which was twofold with respect to standard drug Scheme 1.Synthesis of 1-(6-substituted quinolin-4-yl)ethanone (5a-d).
Scheme 2.Synthetic route of 2-(6-substituted quinolin-4-yl)-1-(4-aryl-1H-1,2,3-triazol-1-yl)propan-2-ol, (9a-l).
Table 1
Antimicrobial activity in MIC (μg/mL) of compounds (9a-l).
Comp. R R [1] C. albicans A. niger
9a H H >250 62.50
9b H CH3 250 62.50
9c H OCH3 >250 31.25
9d Br H >250 31.25
9e Br CH3 >250 15.62
9f Br OCH3 >250 31.25
9g Cl H 250 15.62
9h Cl CH3 250 15.62
9i Cl OCH3 125 7.81
9j F H 125 15.62
9k F CH3 62.50 15.62
9l F OCH3 125 250
Fluconazole 7.81 7.81
Ravuconazole 7.81 31.25
Ravuconazole. Against A. niger, compounds9i(R ¼ Cl, R1 ¼ OCH3) showed excellent activity with MIC 7.81 μg/mL which is comparable with the standard drug Fluconazole and four-fold more than with respect to Ravuconazole. Compound9ialso reported moderate activity against antibacterial strainS. albusand fungal strainC. albicanswith MIC 62.5 and 125 μg/mL, respectively. 2-(6-fluoroquinolin-4-yl)-1-(4-aryl-1H- 1,2,3-triazol-1-yl)propan-2-ol (9j-l), compounds9j(R¼F, R1¼H) and 9k(R¼F, R1¼CH3) showed moderate activity againstC. albicansand excellent activity againstA. nigerwith MIC 15.62μg/mL which is twofold more active with respect to standard antifungal Ravuconazole. The compound9l(R¼F, R1¼OCH3) was found moderately active against C. albicanswith MIC 125μg/mL and less active againstA. nigerwith MIC 250μg/mL.
It is noteworthy that, among the 2-(6-substituted quinolin-4-yl)-1-(4- aryl-1H-1,2,3-triazol-1-yl)propan-2-ol, (9a-l) derivatives, nine com- pounds (9c-k) found comparatively or more active againstA. nigerthan the standard drug Ravuconazole. It was observed that either R¼Br or Cl and R1¼H/CH3/OCH3similarly R¼F and R1¼H or CH3, reported good activity againstA. niger.
2.3. Ergosterol inhibition activity
The antifungal mechanism of action of azole drugs is to disrupt the sterol biosynthetic pathway that leads to ergosterol biosynthesis inhibi- tion. Ergosterol is an important component of the fungal plasma mem- brane, it maintains cell integrity and functionality. The compound which disrupts ergosterol biosynthesis has the potential for antifungal activity [54,55]. The quantitative estimation of ergosterol biosynthesis would be an affirmative way to identify the antifungal activity. Spectrophoto- metric analysis of ergosterol and 24(28)-dehydroergosterol [24(28)DHE]
gives a characteristic peak curve from 240 to 300 nm scan [56]. (Fig. 3).
From the 2-(6-substituted quinolin-4-yl)-1-(4-aryl-1H-1,2,3-triazol-1- yl)propan-2-ol, (9a-l) derivatives, compounds9e,9f,9g,9i, and9kwere studied for ergosterol inhibition activity againstA. nigercells sample at 31.5 μg/mL concentration. The spectrophotometric absorbance profile between 240 and 300 nm of compounds9e,9f,9g,9i, and9kare shown inFig. 3. The absorption spectra revealed that the characteristic peaks of ergosterol present in control are suppressed to a large extent in the compounds9e,9f,9g,9i, and9k. This confirms that ergosterol biosyn- thesis is inhibited in the fungal samples treated with quinolinyl-1,2,3- triazolyl-propan-2-ol derivatives. These results indicate that the ergos- terol was synthesized in control fungal samples (without compound) but was suppressed or not detectable in the rest of the fungal samples which are treated with quinolinyl-1,2,3-triazolyl-propan-2-ol derivatives. This predicts that ergosterol biosynthesis might be inhibited by the quinolinyl-1,2,3-triazolyl-propan-2-ol derivatives.
2.4. Antitubercular activity
All newly synthesized 2-(6-substituted quinolin-4-yl)-1-(4-aryl-1H- 1,2,3-triazol-1-yl)propan-2-ol, (9a-l) derivatives, were screened for antitubercular activity againstMycobacteria tuberculosis, H37 RV strain (ATCC No- 27,294) using Microplate Alamar Blue assay (MABA) [57,58]
The antitubercular drugs Pyrazinamide, Isoniazid, and Rifampicin were used as a positive control (Fig. S1). The MIC was defined as the lowest drug concentration which prevented the color change from blue to pink.
The result of antitubercular activity in Minimum Inhibitory Concentra- tion (MIC) is presented inTable 2.
The results analysis of antitubercular activity suggested that 2-(6- substituted quinolin-4-yl)-1-(4-aryl-1H-1,2,3-triazol-1-yl)propan-2-ol, (9a-l) derivatives showed significant activity against M. tuberculosis H37Rv. Furthermore, the substituents like Br, Cl, and F at the 6-position of the quinoline ring and CH3, and OCH3 at the 4-position of the phenyl ring influence the activity.
The Structure-Activity Relationship study highlighted that, amongst the unsubstituted phenyl ring at the 6-position of quinoline and the substituted phenyl ring at the 4-position of triazole in compounds 1-(4- aryl-1H-1,2,3-triazol-1-yl)-2-(quinolin-4-yl)propan-2-ol (9a-c), com- pound9a(R¼H, R1¼H) exhibited good activity with MIC 9.46μM, which was comparable with respect to antitubercular drug Isoniazid and two-fold more activity with respect to drug Pyrazinamide. The 4-position of 1,2,3-triazole was substituted byp-tolyl in compound9b(R¼H, R1¼ CH3) or 4-methoxy phenyl in compound9c(R¼H, R1¼OCH3), the activity increased by three folds. Compounds 9b and 9c showed
Fig. 3. Spectrophotometric analysis of ergosterol composition ofA. nigerat 31.5μg/mL concentration of compounds9e,9f,9g,9iand9k.
Table 2
Antitubercular activity in MIC inμM (μg/mL) and cytotoxicity activity against HEK cell lines in IC50of compounds (9a-l).
Comp. R R1 M. tuberculosis H37RvμM (μg/mL)
9a H H 9.46(3.12)
9b H CH3 3.37(1.6)
9c H OCH3 3.22(1.6)
9d Br H 2.84(1.6)
9e Br CH3 7.40(3.12)
9f Br OCH3 7.13(3.12)
9g Cl H 4.39(1.6)
9h Cl CH3 4.23(1.6)
9i Cl OCH3 4.06(1.6)
9j F H 8.97(3.12)
9k F CH3 4.41(1.6)
9l F OCH3 8.26(3.12)
Pyrazinamide 25.40 (3.12)
Isoniazid 11.67 (1.6)
Rifampicin 0.97 (0.8)
A. Shinde et al. European Journal of Medicinal Chemistry Reports 7 (2023) 100102
4
outstanding activity with MIC 3.37μM and 3.22 μM which are three times more potent compared to the reference drug Isoniazid. From compounds 1-(4-aryl-1H-1,2,3-triazol-1-yl)-2-(6-bromoquinolin-4-yl) propan-2-ol, (9d-f) compound9d(R¼Br, R1¼H) displayed excellent activity with MIC 2.84μM, which was four-folds more active compare to drug Isoniazid and nine-fold more activity in comparison with the drug Pyrazinamide. The 4-position of the 1,2,3-triazole was substituted byp- tolyl in compound9e (R¼ Br, R1¼ CH3) and 4-methoxy phenyl in compound9f(R¼Br, R1¼OCH3), which showed excellent activity with MIC 7.40μM and 7.13μM, respectively; which are more potent than the reference drugs Isoniazid and Pyrazinamide.
Among the compounds, 1-(4-aryl-1H-1,2,3-triazol-1-yl)-2-(6-chlor- oquinolin-4-yl)propan-2-ol, (9g-i), all three derivatives9g(R¼Cl, R1¼ H),9h(R¼Cl, R1¼CH3) and9i(R¼Cl, R1¼OCH3) showed excellent activity with MIC 4.39, 4.23 and 4.06μM, respectively. All three de- rivatives were three-fold more potent in comparison with the drug Isoniazid. It was noticed that the substitution of the phenyl group byp- tolyl or 4-methoxy phenyl at the 4-position of 1,2,3-triazole there was less effect on the activity. From the compounds 1-(4-aryl-1H-1,2,3-tri- azol-1-yl)-2-(6-fluoroquinolin-4-yl)propan-2-ol, (9j-l), Compound9j(R
¼F, R1¼H) and9l(R¼F, R1¼OCH3) showed excellent activity with MIC 8.97 and 8.26μM, respectively; which are more active than refer- ence drugs Isoniazid and Pyrazinamide. The aryl group at the 4-position of 1,2,3-triazole was substituted byp-tolyl in compound9k, (R¼F, R1¼ CH3) activity increased by two-fold. It showed excellent activity with MIC 4.41μM which is about three times more potent than Isoniazid.
It was noted that all twelve derivatives showed excellent antituber- cular activity with MIC 2.84–9.46μM. All the derivatives were found more active than the reference drugs Isoniazid and Pyrazinamide. From the SAR analysis, it was worth mentioning that, the unsubstituted at the C-6 position of quinoline ring andp-tolyl or 4-methoxy phenyl ring at 4- position of 1,2,3-triazole, bromo at the C-6 position of quinoline and phenyl ring at 4-position of 1,2,3-triazole increases activity. Similarly, the chloro substituent at the C-6 position of quinoline and phenyl orp- tolyl or 4-methoxy phenyl at the 4-position of 1,2,3-triazole, as well as fluoro substituent at the C-6 position of quinoline andp-tolyl group at 4- position of 1,2,3-triazole augmenting the activity.
2.5. Cytotoxicity
Cytotoxicity activity of 2-(6-substituted quinolin-4-yl)-1-(4-aryl-1H- 1,2,3-triazol-1-yl)propan-2-ol, (9a-l) were performed on L929, a normal fibroblast cell line from the subcutaneous connective tissue of mouse.
Since compounds9a-lhave shown antitubercular activity below 10μM, we have used a 12.5μM concentration for cytotoxic studies. L929 cells treated with the compounds9a-lhad no to less cytotoxicity (Table 3).
2.6. Conclusions
In the present study, a new series of 2-(6-substituted quinolin-4-yl)-1- (4-aryl-1H-1,2,3-triazol-1-yl)propan-2-ol, (9a-l) derivatives have been synthesized and screened for antifungal and antitubercular activities.
Eleven derivatives showed good to excellent antifungal activity against A. nigerwith MIC 7.81–62.5μg/mL. AgainstA. niger, the compound 2-(6- chloroquinolin-4-yl)-1-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)
propan-2-ol (9i) showed comparable activity compared to the standard drug Fluconazole. Also, the compounds9e,9g,9h,9j, and9kwere found two folds more potent than the standard drug Ravuconazole. The com- pounds9e,9f,9g,9i, and9kwere further evaluated for the ergosterol biosynthesis inhibition activity, these compounds showed ergosterol biosynthesis inhibition activity. Therefore, the possible antifungal mode of action is ergosterol biosynthesis inhibition. All twelve 2-(6-substituted quinolin-4-yl)-1-(4-aryl-1H-1,2,3-triazol-1-yl)propan-2-ol, (9a-l) de- rivatives showed excellent antitubercular activity againstM. tuberculosis H37Rv strain with MIC 2.84–9.4μM (1.6–3.2μg/mL). The active de- rivatives were further screened for cytotoxicity activity against l929 mousefibroblast cells and found no to less cytotoxicity. The potential antifungal and antitubercular activity suggested that the quinolinyl- 1,2,3-triazolyl-propan-2-ol, (9a-l) derivatives could aid and assist in the development of lead compounds to treat fungal and TB infections.
3. Experimental 3.1. General
The chemicals and solvents used were laboratory-grade and were purified as per literature methods. All the reactions have been monitored by Thin Layer Chromatography (TLC). TLC was performed on the Merck 60 F-254 silica gel plates. Melting points were determined in capillary tubes in a silicon oil bath using a Veego melting point apparatus and were uncorrected. The Infrared spectra were recorded on the Shimadzu FTIR (KBr) - 408 in KBr.1H NMR and13C NMR spectra were recorded on the Bruker or 500 MHz (1HNMR) and 126 MHz (13C NMR), spectrometer instruments. The HRMS spectra were recorded on the Bruker Compass Data Analysis 4.2. The column chromatography was performed on Silica Gel for column chromatography (100–200 mesh) which was supplied by Thermo Fisher Scientific India Pvt. Ltd.
3.1.1. General procedure for 1-azido-2-(6-substituted quinolin-4-yl) propan-2-ol(7a-d)
A mixture of 6-bromo-4-(2-methyloxiran-2-yl)quinoline, (6b), so- dium azide, and ammonium chloride in ethanol was refluxed for 4–5 h.
After complete conversion, ethanol was distilled under a vacuum, and the residue was dissolved in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and distilled on a rotary evaporator. The crude product was purified by column chroma- tography using ethyl acetate: hexane (3:7) as eluent to obtain pure product 1-azido-2-(6-substituted quinolin-4-yl)propan-2-ol, (7a-d).
1-Azido-2-(quinolin-4-yl)propan-2-ol(7a): Yield: 85%; Mp. 68C;
1H NMR (500 MHz, CDCl3)δ¼8.67 (d,J¼4.6 Hz, 1H, Ar–H), 8.62 (d,J
¼8.7 Hz, 1H, Ar–H), 8.08 (d,J¼8.4 Hz, 1H, Ar–H), 7.65 (t,J¼7.6 Hz, 1H, Ar–H), 7.56–7.50 (m, 1H, Ar–H), 7.43 (d,J¼4.7 Hz, 1H, Ar–H), 4.00 (d,J¼12.5 Hz, 1H, CH2–N3), 3.73 (d,J¼12.5 Hz, 1H, CH2–N3), 1.85 (s, 3H, CH3);13C NMR (126 MHz, CDCl3) δ149.6, 149.1, 130.5, 129.0, 126.4, 126.1, 125.9, 118.6, 75.6, 60.7, 27.0.
1-Azido-2-(6-bromoquinolin-4-yl) propan-2-ol (7b): Yield: 78%;
Mp. 70C;1H NMR (500 MHz, CDCl3)δ8.88 (d,J¼2.1 Hz, 1H, Ar–H), 8.73 (d,J¼4.7 Hz, 1H, Ar–H), 7.95 (d,J¼9.0 Hz, 1H, Ar–H), 7.74 (dd,J
¼9.0, 2.1 Hz, 1H, Ar–H), 7.39 (d,J¼4.7 Hz, 1H, Ar–H), 4.00 (d,J¼ 12.5 Hz, 1H, CH2–N3), 3.72 (d,J¼12.5 Hz, 1H, CH2–N3), 1.83 (s, 3H, CH3);13C NMR (126 MHz, CDCl3)δ149.9, 148.4, 147.8, 132.6, 132.1, 128.6, 127.2, 120.7, 119.2, 75.5, 60.6, 27.2.
1-Azido-2-(6-chloroquinolin-4-yl) propan-2-ol (7c): Yield: 80%;
Mp. 75C;1H NMR (500 MHz, CDCl3)δ8.73 (d,J¼4.7 Hz, 1H, Ar–H), 8.70 (d,J¼2.2 Hz, 1H, Ar–H), 8.02 (d,J¼9.0 Hz, 1H, Ar–H), 7.61 (dd,J
¼9.0, 2.3 Hz, 1H, Ar–H), 7.40 (d,J¼4.7 Hz, 1H, Ar–H), 4.01 (d,J¼ 12.5 Hz, 1H, CH2–N3), 3.72 (d,J¼12.5 Hz, 1H, CH2–N3), 1.83 (s, 3H, CH3);13C NMR (126 MHz, CDCl3)δ149.8, 148.4, 147.6, 132.3, 132.0, 130.0, 126.6, 125.3, 119.2, 75.5, 60.6, 27.1.
1-Azido-2-(6-fluoroquinolin-4-yl)propan-2-ol (7d): Yield: 75%;
Mp. 60C;1H NMR (500 MHz, CDCl3)δ8.64 (dd,J¼6.4, 3.9 Hz, 1H, Table 3
Cell viability (%) against mouse embryonicfibroblast cells (L929).
Compound Cell viability (%) Compound Cell viability (%)
9a 100 9g 58.62
9b 62.90 9h 60.12
9c 80.33 9i 57.35
9d 56.51 9j 66.13
9e 60.12 9k 83.94
9f 76.14 DMSO 100
Ar–H), 8.37 (dd,J¼11.5, 2.5 Hz, 1H, Ar–H), 8.07 (dd,J¼9.2, 5.7 Hz, 1H, Ar–H), 7.43 (dd,J¼9.0, 7.8 Hz, 1H, Ar–H), 7.38 (d,J¼4.5 Hz, 1H, Ar–H), 3.99 (d,J¼12.5 Hz, 1H, CH2–N3), 3.70 (d,J¼12.5 Hz, 1H, CH2–N3), 1.82 (s, 3H, CH3);13C NMR (126 MHz, CDCl3)δ160.8, 158.8, 148.7, 146.2, 132.8, 126.8, 119.4, 119.2, 110.4, 110.2, 75.5, 60.5, 26.9.
3.1.2. General procedure 2-(6-bromoquinolin-4-yl)-1-(4-phenyl-1H- 1,2,3-triazol-1-yl)propan-2-ol(9a-l)
A mixture of 1-azido-2-(6-bromoquinolin-4-yl)propan-2-ol, (7d), ethynylbenzene (8a), copper sulfate pentahydrate, and sodium ascorbate in DMF: water (2:1) was stirred at room temperature for 12–18 h. After the complete conversion of the reactant (TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate,filtered and the solvent was evaporated on a rotary evaporator. The crude product was purified by column chromatography using ethyl acetate:hexane (3:7) as eluent furnished 2-(6-bromoquinolin-4-yl)-1-(4-phenyl-1H-1,2,3-triazol- 1-yl)propan-2-ol (9d). All the derivatives were synthesized using a similar experimental protocol.
1-(4-Phenyl-1H-1,2,3-triazol-1-yl)-2-(quinolin-4-yl)propan-2-ol (9a): Yield: 72%; Mp. 210C;1H NMR (500 MHz, CDCl3)δ1H NMR (500 MHz, CDCl3)δ8.81 (d,J¼4.5 Hz, 2H, Ar–H, Triazole-H), 8.10 (dd,J¼ 8.3, 3.2 Hz, 1H, Ar–H), 8.04 (d,J¼6.2 Hz, 1H, Ar–H), 7.79–7.72 (m, 2H, Ar–H), 7.73–7.66 (m, 1H, Ar–H), 7.60 (dd,J¼9.0, 4.7 Hz, 1H, Ar–H), 7.57 (t,J¼4.5 Hz, 1H, Ar–H), 7.42–7.33 (m, 2H, Ar–H), 7.32–7.24 (m, 1H, Ar–H), 6.11 (s, 1H), 4.95 (q,J¼14.1 Hz, 2H), 1.72 (s, 3H);13C NMR (126 MHz, CDCl3) δ154.8, 154.7, 154.6, 154.0, 151.6, 135.6, 135.7, 135.4, 133.6, 132.8, 131.3, 131.1, 130.8, 130.3, 127.0, 126.8, 123.6, 79.0, 64.1, 31.3; HRMS:m/z¼331.1554 (MþH)þ.
1-(4-(p-tolyl)-1H-1,2,3-triazol-1-yl)-2-(Quinolin-4-yl)propan-2-ol (9b): Yield: 70%; Mp. 198C;1H NMR (500 MHz, CDCl3)δ8.86 (d,J¼ 8.6 Hz, 1H, Ar–H), 8.84 (d,J¼4.6 Hz, 1H, Ar–H), 8.40 (s, 1H, Triazole- H), 8.09 (dd,J¼8.4, 0.9 Hz, 1H, Ar–H), 7.81–7.75 (m, 1H, Ar–H), 7.72 (d,J¼8.1 Hz, 2H, Ar–H), 7.66 (ddd,J¼8.3, 6.9, 1.2 Hz, 1H, Ar–H), 7.60 (d,J¼4.6 Hz, 1H, Ar–H), 7.25 (d,J¼8.0 Hz, 2H, Ar–H), 6.24 (s, 1H), 4.99 (d,J¼14.1 Hz, 1H), 4.91 (d,J¼14.1 Hz, 1H), 2.33 (s, 3H), 1.71 (s, 3H);13C NMR (126 MHz, CDCl3)δ155.0, 154.0, 151.0, 142.3, 135.5, 134.6, 133.9, 133.2, 131.3, 130.9, 130.3, 127.8, 127.6, 124.3, 124.2, 79.0, 64.1, 31.9, 26.1; HRMS:m/z¼345.1518 (MþH)þ.
1-(4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-2-(quinolin-4-yl) propan-2-ol(9c): Yield: 70%; Mp. 110C;1H NMR (500 MHz, CDCl3)δ 8.85 (dd,J¼12.7, 6.6 Hz, 2H, Ar–H), 8.34 (s, 1H, Triazole-H), 8.09 (dd, J¼8.4, 0.8 Hz, 1H, Ar–H), 7.84–7.72 (m, 3H, Ar–H), 7.70–7.62 (m, 1H, Ar–H), 7.60 (d,J¼4.6 Hz, 1H, Ar–H), 7.01 (d,J¼8.8 Hz, 2H, Ar–H), 6.24 (s, 1H), 4.94 (dd,J¼41.4, 14.1 Hz, 2H), 3.79 (s, 3H), 1.71 (s, 3H);
13C NMR (126 MHz, CDCl3)δ164.1, 155.0, 154.0, 150.8, 135.5, 133.9, 131.7, 131.3, 130.9, 128.6, 127.3, 127.0, 124.3, 124.2, 119.5, 79.0, 64.1, 60.4, 31.9.; HRMS:m/z¼361.1670 (MþH)þ.
2-(6-Bromoquinolin-4-yl)-1-(4-phenyl-1H-1,2,3-triazol-1-yl) propan-2-ol(9d): Yield: 68%; Mp. 208C;1H NMR (500 MHz, DMSO‑d6) δ9.13 (d,J¼2.0 Hz, 1H, Ar–H), 8.91 (d,J¼4.6 Hz, 1H, Ar–H), 8.45 (s, 1H, Triazole-H), 8.05 (d,J¼8.9 Hz, 1H, Ar–H), 7.92 (dd,J¼8.9, 2.1 Hz, 1H, Ar–H), 7.87 (d,J¼7.2 Hz, 2H, Ar–H), 7.63 (d,J¼4.7 Hz, 1H, Ar–H), 7.48 (t,J¼7.7 Hz, 2H, Ar–H), 7.37 (t,J¼7.4 Hz, 1H, Ar–H), 6.44 (s, 1H), 5.00 (d,J¼14.1 Hz, 1H), 4.92 (d,J¼14.1 Hz, 1H), 1.76 (s, 3H);13C NMR (126 MHz, DMSO‑d6)δ150.9, 149.5, 147.9, 146.3, 132.7, 132.3, 131.2, 129.5, 129.3, 128.2, 127.8, 125.7, 123.3, 120.5, 119.8, 74.8, 59.7, 27.5; HRMS:m/z¼409.0671 (MþH)þ; 411.0650 (Mþ2þH)þ.
2-(6-Bromoquinolin-4-yl)-1-(4-(p-tolyl)-1H-1,2,3-triazol-1-yl) propan-2-ol(9e): Yield: 66%; Mp. 188C;1H NMR (500 MHz, CDCl3)δ 9.15 (d,J¼1.2 Hz, 1H, Ar–H), 8.87 (d,J¼4.4 Hz, 1H, Ar–H), 8.08–7.94 (m, 2H, Ar–H, Triazole-H), 7.82 (dd,J¼8.9, 1.6 Hz, 1H, Ar–H), 7.71 (d, J¼7.9 Hz, 2H, Ar–H), 7.56 (d,J¼4.4 Hz, 1H, Ar–H), 7.24 (d,J¼7.9 Hz, 2H, Ar–H), 6.21 (s, 1H), 4.94 (d,J¼4.7 Hz, 2H), 2.40 (s, 3H), 1.77 (s, 3H);13C NMR (126 MHz, CDCl3)δ155.1, 154.9, 153.9, 152.7, 151.8, 142.4, 137.1, 134.2, 132.7, 132.2, 130.3, 126.4, 126.2, 125.1, 124.2,
79.3, 64.2, 31.5, 26.0; HRMS:m/z ¼423.0827 (Mþ H)þ; 425.0802 (Mþ2þH)þ.
2-(6-Bromoquinolin-4-yl)-1-(4-(4-methoxyphenyl)-1H-1,2,3-tri- azol-1-yl)propan-2-ol(9f): Yield: 66%; Mp. 192C;1H NMR (500 MHz, CDCl3)δ9.04 (s, 1H, Triazole-H), 8.81–8.72 (m, 1H, Ar–H), 7.93 (dd,J¼ 8.9, 3.1 Hz, 1H, Ar–H), 7.86 (d,J¼3.8 Hz, 1H, Ar–H), 7.75–7.68 (m, 1H, Ar–H), 7.64 (dd,J¼8.7, 3.1 Hz, 2H, Ar–H), 7.46 (t,J¼3.9 Hz, 1H, Ar–H), 6.87 (dd,J¼8.7, 3.1 Hz, 2H, Ar–H), 6.13 (d,J¼4.0 Hz, 1H), 4.89–4.78 (m, 2H), 3.76 (d,J¼3.2 Hz, 3H), 1.67 (d,J¼3.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 164.2, 154.9, 153.9, 152.7, 151.6, 137.0, 133.9, 133.7, 132.3, 131.7, 128.2, 125.8, 125.0, 124.3, 119.0, 79.3, 64.3, 60.1, 31.5; HRMS:m/z¼439.0775 (MþH)þ; 441.0751 (Mþ2þH)þ.
2-(6-Chloroquinolin-4-yl)-1-(4-phenyl-1H-1,2,3-triazol-1-yl) propan-2-ol(9g): Yield: 70%; Mp. 206C;1H NMR (500 MHz, DMSO‑d6) δ8.93 (d,J¼2.3 Hz, 1H, Ar–H), 8.85 (d,J¼4.6 Hz, 1H, Ar–H), 8.43 (s, 1H, Triazole-H), 8.08 (d,J ¼ 9.0 Hz, 1H, Ar–H), 7.86–7.80 (m, 2H, Ar–H), 7.77 (dd,J¼9.0, 2.3 Hz, 1H, Ar–H), 7.59 (d,J¼4.7 Hz, 1H, Ar–H), 7.43 (t,J¼7.7 Hz, 2H, Ar–H), 7.33 (d,J¼7.4 Hz, 1H, Ar–H), 6.39 (s, 1H), 4.92 (dd,J¼45.8, 14.1 Hz, 2H), 1.72 (s, 3H);13C NMR (126 MHz, DMSO‑d6)δ150.9, 149.6, 147.7, 146.3, 137.6, 132.6, 131.2, 131.0, 129.8, 129.3, 128.2, 127.2, 126.3, 125.6, 123.3, 120.5, 119.6,74.7, 59.7, 27.4; HRMS:m/z¼ 365.1169 (MþH)þ; 367.1145 (Mþ2þH)þ.
2-(6-Chloroquinolin-4-yl)-1-(4-(p-tolyl)-1H-1,2,3-triazol-1-yl) propan-2-ol(9h): Yield: 66%; Mp. 186C;1H NMR (500 MHz, DMSO‑d6) δ8.94 (d,J¼6.5 Hz, 1H, Ar–H), 8.87–8.77 (m, 1H, Ar–H), 8.08 (s, 1H, Triazole-H), 8.01 (d,J¼8.2 Hz, 1H, Ar–H), 7.73–7.62 (m, 3H, Ar–H), 7.58–7.50 (m, 1H, Ar–H), 7.22 (t,J¼7.6 Hz, 2H, Ar–H), 6.22 (d,J¼8.1 Hz, 1H), 4.92 (t,J¼8.1 Hz, 2H), 2.37 (d,J¼8.2 Hz, 3H), 1.75 (d,J¼ 8.2 Hz, 3H);13C NMR (126 MHz, DMSO)δ150.0, 149.0, 147.6, 146.8, 137.5, 132.1, 131.6, 129.5, 129.3, 127.8, 126.8, 125.6, 125.3, 121.5, 119.4, 74.3, 59.3, 26.6, 21.1; HRMS: m/z ¼ 379.1330 (M þ H)þ; 379.1306 (Mþ2þH)þ.
2-(6-Chloroquinolin-4-yl)-1-(4-(4-methoxyphenyl)-1H-1,2,3-tri- azol-1-yl)propan-2-ol(9i): Yield: 65%; Mp. 192C;1H NMR (500 MHz, DMSO‑d6)δ8.93 (s, 1H, Triazole-H), 8.82 (dd, J¼ 4.5, 1.7 Hz, 1H, Ar–H), 8.07 (dd,J¼9.0, 1.8 Hz, 1H, Ar–H), 7.94 (d,J¼2.5 Hz, 1H, Ar–H), 7.68 (ddd,J¼22.0, 8.9, 2.1 Hz, 3H, Ar–H), 7.53 (dd,J¼4.5, 1.9 Hz, 1H, Ar–H), 6.93 (dd,J¼8.7, 1.9 Hz, 2H, Ar–H), 6.20 (d,J¼2.6 Hz, 1H), 4.91 (d,J¼7.6 Hz, 2H), 3.83 (d,J¼1.9 Hz, 3H), 1.74 (s, 3H);13C NMR (126 MHz, DMSO‑d6)δ159.4, 150.1, 149.2, 147.7, 146.8, 132.2, 131.8, 129.7, 127.0, 126.9, 125.7, 123.4, 121.2, 119.6, 114.2, 74.5, 59.5, 55.3, 26.7; HRMS:m/z¼395.1278 (MþH)þ; 397.1255 (Mþ2þH)þ.
2-(6-Fluoroquinolin-4-yl)-1-(4-phenyl-1H-1,2,3-triazol-1-yl) propan-2-ol(9j): Yield: 68%; Mp. 202C;1H NMR (500 MHz, DMSO‑d6) δ 8.81 (dd, J ¼ 9.5, 4.4 Hz, 1H, Ar–H), 8.65–8.54 (m, 1H, Ar–H), 8.19–8.10 (m, 1H, Ar–H), 8.09–8.03 (m, 1H, Ar–H), 7.80 (t,J¼8.7 Hz, 2H, Ar–H), 7.55 (dt,J¼15.2, 7.6 Hz, 2H, Ar–H), 7.46–7.36 (m, 2H), Ar–H, 7.36–7.26 (m, 1H, Ar–H), 6.18 (d,J¼9.8 Hz, 1H), 4.94 (t,J¼ 10.7 Hz, 2H), 1.75 (d,J¼10.1 Hz, 3H);13C NMR (126 MHz, DMSO‑d6)δ 160.6, 158.7, 149.4, 149.4, 149.3, 146.9, 146.5, 133.1, 133.0, 130.8, 128.8, 128.0, 127.0, 126.9, 125.6, 122.1, 119.4, 119.2, 119.0, 110.7, 110.5, 74.5, 59.4, 26.5; HRMS:m/z¼349.1467 (MþH)þ.
2-(6-Fluoroquinolin-4-yl)-1-(4-(p-tolyl)-1H-1,2,3-triazol-1-yl) propan-2-ol(9k): Yield: 65%; Mp. 212C;1H NMR (500 MHz, DMSO‑d6) δ8.80 (d,J¼4.6 Hz, 1H), 8.58 (dd,J¼11.7, 2.4 Hz, 1H), 8.13 (dd,J¼ 9.2, 6.0 Hz, 1H), 8.03 (s, 1H), 7.67 (d,J¼8.0 Hz, 2H), 7.54 (dd,J¼11.0, 3.0 Hz, 2H), 7.21 (d,J¼7.9 Hz, 2H), 6.18 (s, 1H), 4.91 (q,J¼14.1 Hz, 2H), 2.37 (s, 3H), 1.73 (s, 3H);13C NMR (126 MHz, DMSO‑d6)δ160.6, 158.6, 149.4, 149.3, 146.9, 146.5, 137.6, 133.1, 133.0, 129.5, 128.0, 127.0, 126.9, 125.5, 121.6, 119.4, 119.1, 118.9, 110.7, 110.5, 74.5, 59.3, 26.5, 21.3; HRMS:m/z¼363.1625 (MþH)þ.
2-(6-Fluoroquinolin-4-yl)-1-(4-(4-methoxyphenyl)-1H-1,2,3-tri- azol-1-yl)propan-2-ol(9l): Yield: 65%; Mp. 180C;1H NMR (500 MHz, DMSO‑d6)δ8.73 (s, 1H), 8.50 (d,J¼9.0 Hz, 1H), 8.07 (s, 1H), 7.84 (dd, J¼3.2, 1.7 Hz, 1H), 7.63 (dd,J¼6.3, 2.2 Hz, 2H), 7.46 (s, 2H), 6.86 (dd,
A. Shinde et al. European Journal of Medicinal Chemistry Reports 7 (2023) 100102
6
J¼6.3, 2.2 Hz, 2H), 6.04 (s, 1H), 4.83 (d,J¼3.9 Hz, 2H), 3.75 (dd,J¼ 4.3, 2.3 Hz, 3H), 1.66 (s, 3H);13C NMR (126 MHz, DMSO‑d6)δ155.7, 154.4, 153.7, 144.4, 144.4, 144.2, 141.9, 141.5, 128.1, 128.0, 121.9, 118.4, 116.1, 114.4, 114.2, 114.0, 109.2, 105.6, 105.5, 69.5, 54.2, 50.3, 21.4; HRMS:m/z¼379.1572 (MþH)þ.
3.1.3. Antifungal activity
Thein vitroantifungal activity of the synthesized derivatives was done by well diffusion method against Candida albicans (NCIM 3100) and Aspergillus niger(NCIM 504) [52,53]. The fungal strains were obtained from NCIM, NCL, Pune, India. The pure cultures were maintained by routine sub-culturing after every one-month interval on Potato Dextrose Agar slants (Hi-Media lab. Pvt. Ltd, Mumbai, India). Mueller Hinton agar plates were prepared by pouring 20 mL in each sterile petri - plate for fungal assay and allowed to solidify. During the assay, standard fungal cultures were grown on Potato-Dextrose broth. Five hundred microliters of 48–72 h old fresh fungal spore suspension were spread on the agar plates using a sterile cotton swab to get uniform growth. With the help of well borer, 5 mm diameter wells were punched on the agar plates. The synthesized compounds were dissolved in DMSO. The wells werefilled with 80μL of the samples. As a vehicle control, DMSO was added to one agar plate. A standard plate with Fluconazole and Ravuconazole was used as a positive control. The plates were incubated for a period of 48–72 h at 30C. After the incubation period, the plates were observed for a clear zone of inhibition. The zones of inhibition were measured in mm using a measuring scale and the mean was calculated. The experiments were carried out infive replicates.
The micro-dilution susceptibility test in Sabouraud Liquid Medium (Oxoid) was used for the determination of minimum inhibition concen- tration (MIC). The stock solution of the test compounds, Fluconazole and Ravuconazole was prepared in DMSO at a concentration of 1000μg/mL.
Two-fold serial dilutions of the test compounds solutions were prepared using broth. Thefinal concentration of the solutions was 500, 250, 125, 62.5, 31.25, 15.62, 7.81, and 3.90μg/mL. The tubes were inoculated with the test organisms, grown in the Potato-Dextrose broth. The tubes were kept for incubation for 48–72 h at 30C. The lowest concentration showing no growth was considered as minimum inhibition concentration (MIC). All experiments were carried out in triplicates.
3.1.4. Antitubercular assay
The antitubercular activity of compounds was assessed against M. tuberculosisH37 RV (ATCC No- 27,294) strain using microplate Almar Blue assay (MABA) [57,58]. Briefly, 200μL of sterile de-ionized water was added to all outer perimeter wells of the sterile 96 wells plate to minimize evaporation of medium in the test wells during incubation. The 96 wells plate received 100μL of the Middlebrook 7H9 broth and serial dilution of compounds was made directly on a plate. Thefinal compound concentrations tested were 100 to 0.2μg/mL. Plates were covered and sealed with parafilm and incubated at 37C forfive days. 25μL of freshly prepared 1:1 mixture of Almar Blue reagent and 10% tween 80 was added to the plate and incubated for 24 h. The blue color in the well was interpreted as no bacterial growth, and the pink color was scored as growth. Further, the MIC was defined as the lowest drug concentration which prevented the color change from blue to pink.
Conflicts of interest
There are no conflicts to declare.
Data availability
Data will be made available on request.
Acknowledgments
ADS expresses his gratefulness to the CSIR-India, for the SRF
fellowship (File No.08/319(000 4)/2017-EMR-1). The authors would like to acknowledge S. P. Mandali Pune and Late. Dr. T. R. Ingale's family for providing infrastructure facilities. The authors would like to thank CIF-SPPU, Pune, and IISER, Pune for spectral analysis. S. P. Mandali's Bhide Foundation Pune has been acknowledged for lending support to their biological activities.
Appendix A. Supplementary data
Supplementary data to this article can be found online athttps://
doi.org/10.1016/j.ejmcr.2023.100102.
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