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Synthesis of fluoro-rich pyrimidine-5-carbonitriles as antitubercular agents against H37Rv receptor

  • Khushal M. Kapadiya , Kishor M. Kavadia , Vijay M. Khedkar , Piyush V. Dholaria , Amita J. Jivani and Ranjan C. Khunt EMAIL logo
Published/Copyright: June 15, 2022
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 28 Issue 1

Abstract

The purpose of this study was to prepare various derivatives of 4-amino-2-(3-fluoro-5-(trifluoromethyl)phenyl)-6-arylpyrimidine-5-carbonitrile (6a–6h) using a three-step procedure. The derivatives were screened in vitro for activity against Mycobacterium tuberculosis strain H37Rv. The activity was expressed as the minimum inhibitory concentration (MIC) in μg/mL (μM). Eight compounds showed activity against Mtb H37Rv, and among them, 6f showed the best value of MIC, IC50 (53 μM) and IC90 (62 μM). Minimum bactericidal concentration of compound 6f was higher than its MIC and was more time-dependent than the concentration. Compound 6f was more active against M. tuberculosis H37Rv under low oxygen than metronidazole and did not show good potency in different treatments and non-tuberculous mycobacteria. Furthermore, a molecular docking study against mycobacterial enoyl-ACP reductase (InhA) could provide valuable insights into the plausible mechanism of action, which could set the theme for lead optimization.

Graphical abstract

Keywords: pyrimidine-5-carbonitriles; antitubercular activity; trifluoro functionality; molecular docking

1 Introduction

Tuberculosis (TB) is one of the largest problems facing modern health services, and more than two billion people are currently infected with Mycobacterium tuberculosis [1]. According to World Health Organization 2019 reports, in the 5 years from 2018 to 2022, 40 million people will need to be treated for TB disease, and breakthrough effects for 2020 are a 35% reduction in the number of TB deaths and a 20% reduction in the TB incidence rate. India stands among the top three nations for most active cases globally, with a 27% growth rate in TB [2,3]. Surprisingly in 2018, a 78% rate was observed for multidrug-resistant TB. Latent-to-active TB transition risk has reached 50% among people with acute immunodeficiency syndrome and is about 10% among the rest of the population [4,5,6,7].

All the above facts initiated the search for principally new anti-TB drugs. Nucleoside derivatives, among which potent antiviral and anticancer agents have been found, can be regarded as a promising class for this search. However, the anti-TB activity of nucleosides has been unknown until recently. In the twenty-first century only, many examples of scientific literature were available on a few groups of modified nucleosides that displayed in vitro antimycobacterial activity [8,9]. In studies to date, nitrogen-bearing scaffolds served as the best pharmacophore [10], particularly, pyrimidine, an integral part of DNA and RNA that imparts diverse pharmacological properties. Incorporating the trifluoromethyl functionalities into nitrogen-based heterocycles enhances the medicinal functionalities reported in recent years [11]. The structure–activity relationship studies of 5-modified pyrimidine nucleosides with diverse substituents proved that many such compounds showed the best antimycobacterial properties against M. tuberculosis, M. avium, and M. bovis [12].

The fluoro-containing constituents of nitrogen-based classes of compounds (Moxifloxacin, Levofloxacin, Ofloxacin, and Gatifloxacin) are potent inhibitors of the DNA gyrase enzyme and are proven for better medicinal agents. Several of these were shown to be active on M. tuberculosis bacilli based on recent trends to check the potency of the scaffolds, that is, target-based TB drug discovery [13].

The above facts state that utilizing pyrimidine core derivatives is a relatively effective means to counter TB [14], further reinforcing our belief that pyrimidine 5-carbonitriles with difluorinated functionality could be a lead compound in our effort to discover new potent anti-TB agents. In the present article, we report the synthesis and antimycobacterial activity of novel 4-amino-2-(3-fluoro-5-(trifluoromethyl)phenyl)-6-arylpyrimidine-5-carbonitrile derivatives against M. tuberculosis strain H37Rv, followed by a molecular docking study against mycobacterial enoyl-acyl carrier protein (ACP) reductase (InhA).

2 Results and discussion

2.1 Chemistry

The synthesis of novel molecules is always carried out by simple reaction procedures using commercially available reactants and/or reagents. To design and prepare new pyrimidine-5-carbonitrile compounds, in this research, we want to use some novel fluoro-rich aromatic compounds to react with various arylidenes to give fresh trifluoro rich pyrimidine-5-carbonitrile compounds. Nowadays, people generally know that trifluoro methylated compounds are one of the most potentially important and efficient probes in finding new biological compounds because of the unique role of the CF 3 group in enhancing the bioactivity of organic molecules. According to this idea, we wanted to synthesize some 4-amino-2-(3-fluoro-5-(trifluoromethyl)phenyl)-6-arylpyrimidine-5-carbonitrile (6a–6h) compounds with trifluoromethyl group from the unique reaction of methyl 3-fluoro-5-(trifluoromethyl)benzenecarbimidothioate, various substituted arylidenes, and malononitrile in a three-step procedure. Initially, we studied the reaction from starting materials of methyl 3-fluoro-5-(trifluoromethyl)benzenecarbimidothioate (1) and ammonium acetate in acetonitrile (ACN) under room temperature (RT) stirring to obtain intermediate (2). The second step includes the arylidene formation by the reaction between aromatic aldehyde and malononitrile to afford an easily accessible intermediate 5a–h. The final products 6a–6h were synthesized by the reaction of intermediates 2 and 5a–h under refluxing conditions using glacial acetic acid as a catalyst. No matter what position has substituted the group of arylidene parts, all the reactions could be carried out smoothly. Moreover, in this synthesis, trifluoromethyl was successfully introduced into the aryl pyrimidine compounds, and these compounds may be potential drug precursor compounds. All the obtained new 4-amino-2-(3-fluoro-5-(trifluoromethyl)phenyl)-6-arylpyrimidine-5-carbonitriles (6a–6h) are off-white solids, and their structures were established by spectroscopic data, especially infrared (IR) spectroscopy, 1H NMR (nuclear magnetic resonance spectroscopy), 13C NMR, and mass spectroscopy (MS) (Scheme 1).

Scheme 1 Synthetic route for the preparation of title compounds (6a–6h). Reaction conditions – (a) ammonium acetate, ACN, 6 h, and RT; (b) piperidine, methanol, 10–15 min, and RT; (c) glacial acetic acid, ACN, refluxed, 70°C, and 5–6 h.
Scheme 1

Synthetic route for the preparation of title compounds (6a–6h). Reaction conditions – (a) ammonium acetate, ACN, 6 h, and RT; (b) piperidine, methanol, 10–15 min, and RT; (c) glacial acetic acid, ACN, refluxed, 70°C, and 5–6 h.

2.2 Spectroscopic analysis

The structure of synthesized compounds 6a–6h was confirmed based on spectral data. The IR spectrum of compound 6a–6h showed a strong absorption band at 3,718–3,412 cm−1 due to N–H stretching and primary amine. The absorption band appeared at 3,295–3,010 cm−1 due to stretching vibrations of aromatic hydrogen and the absorption band at 2,248–2,178 cm−1 due to stretching vibration to C≡N in the nitrile group. The absorption peak was observed at 1,678–1,545 cm−1 in the C…C stretching of the aromatic ring. Moreover, absorption bands that appeared in compound 6a–6h at 1,384–1,298 cm−1 indicated the C–N linkage present in the pyrimidine ring title compound. In 1H NMR spectra, the appearance of singlet peaks in compounds 6a–6h showed a characteristic value at δ = 7.22–8.66 ppm due to the presence of aromatic proton. The presence of Ar-NH̲2 showed a singlet peak at 3.35–5.84 ppm. Six protons of Ar-N(CH̲3)2 displayed singlet at δ = ∼3.18 ppm. The presence of Ar-OCH̲3 showed a singlet peak at ∼2.78 ppm. The remaining substituents protons were in good agreement with theoretical values.13C NMR spectra helped us to identify the formation of the final adducts. The characteristic value around δ = 122 ppm showed the presence of a trifluoromethyl group attached with an aromatic ring and exhibited a peak around δ = 130 ppm. The aromatic ring carbon and heterocyclic ring carbons were in decent covenants with the theoretical values. The mass spectrum revealed a molecular ion peak in compound 6a–6h at m/z = 437–374 in mass spectra. The molecular ion peak was in agreement with the proposed molecular weight and elemental analysis.

3 Biological evaluation

3.1 In vitro antimicrobial activity against Mycobacterium tuberculosis H37Rv

M. tuberculosis H37Rv study was carried out under aerobic conditions for the evaluation of compounds 6a–6h is a part of the contract (contract number HHSN272201100009I/HHSN27200002 A14) with the NIAID division, USA, and Department of Chemistry, the Saurashtra University, Rajkot. The standard screening (primary in vitro) was evaluated by defining the MIC, IC50, and IC90 values (concentrations required for growth inhibition 50 and 90%, respectively) [15].

As per the data shown in Table 1, out of eight tested diverse molecules against M. tuberculosis H37Rv, 6f was found to have excellent MIC (85 µM), IC50 (53 µM), and IC90 (62 µM). Remarkably, –CN functionality at the para position of aromatic substituents might affect the potency of compound 6f. Replacing the ortho/para R group with –X or electron withdrawing groups (EWG) and/or electron donating groups (EDG) led to a dropping in antimycobacterial activity (MIC > 50–200 µM).

Table 1

Antimycobacterial activity against M. tuberculosis H37Rv of 6a–6h (aerobic conditions) [16]

Compound MIC (µM) IC50 (µM) IC90 (µM) Glide score Glide energy (kcal/mol) H-Bonding (Å) pi–pi (π–π) stacking (Å)
6a >50 >50 >50 −8.759 −41.404 — Tyr158(2.107)
6b >50 >50 >50 −8.543 −40.726 — Tyr158(2.178)
6c >200 >200 >200 −7.269 −34.059 — Tyr158(2.21)
6d >50 >50 >50 −8.542 −40.34 — Tyr158(2.031)
6e >50 >50 >50 −8.483 −39.55 — Tyr158(2.611)
6f 85 53 62 −9.387 −43.555 Thr17(2.546), Ser20(2.533) Tyr158(2.566)
6g >50 >50 >50 −8.789 −40.055 — Tyr158(2.027)
6h >50 >50 >50 −8.476 −40.317 — Tyr158(2.411)
Rifampicin 0.0065 0.0036 0.0071

Finally, compound 6f was identified as potent in anti-TB activity and preceded further antimycobacterial studies. It was subjected to the advanced MIC, IC50, and IC90 (repeated at lower starting concentrations), MIC under low oxygen, minimal bactericidal concentration (MBC) [17], cytotoxicity, and intracellular activity.

The bactericidal activity of 6f was measured against Mtb H37Rv developed in aerobic environments. For compounds 6f, the effect of time outweighs that of concentration; hence, these show time-dependent properties, which are considerably linked with an optimal. As shown in Tables 1 and 3, the aerobic condition was maintained using uniform aeration in the media, and under normal conditions, the static oxygen level influenced only the upper part of the media. That is why the MIC shown in the aerobic condition is 85, and the same for normal conditions is 160 µM for compound 6f. Moreover, the performance based on the controls indicates if the assay is working properly. It must be noted here that there is a dependency on oxygen-level concentration in aerobic and normal conditions [18].

Table 2

The bactericidal activity (MBC) of compounds 6f [16]

Compound MIC (µM) MBC (µM) Concentration dependent Time-dependent
6f 85 100 N Y

The antimicrobial activity of compounds against M. tuberculosis H37Rv grown under hypoxic conditions is assessed using the low oxygen recovery assay. Bacteria are first adapted to low oxygen conditions and then exposed to compounds under hypoxia; this is followed by a period of outgrowth in aerobic conditions, free drug supreme concentration to MIC quotient. Due to the time-dependent effect of molecule 6f, the time effect is more, and free drug concentrations outstandingly overhead the MIC to a specific ratio of the dosing interim (Table 2) [19]. Table 3 shows that 6f displayed better MIC (160 µM), IC50 (52 µM), and IC90 (90 µM) than the metronidazole in normal conditions. Therefore, we presume that tested compound 6f shows their best activity against five Mtb strains, i.e., two isoniazid-resistant strains (INH-R1 and INH-R2), two rifampicin-resistant strains (RIF-R1 and RIF-R2) and a fluoroquinolone-resistant strain (FQ-R1) and some non-tuberculous mycobacteria, i.e., M. avium and M. abscessus) under aerobic conditions [20] (see supplementary file for more details).

Table 3

Antimycobacterial activities (Mtb H37Rv) of compounds 6f under low oxygen [16]

Compound Low oxygen (µM) Normal oxygen (µM)
MIC IC50 IC90 MIC IC50 IC90
6f >200 160 >200 160 52 90
Rifampicin 0.018 0.0027 0.0067 0.021 0.0057 0.011
Metronidazole 200 30 64 >200 >200 >200

3.2 Molecular docking

To rationalize the promising antitubercular activity demonstrated by the pyrimidine-5-carbonitriles (6a–6h) in the in vitro cell-based assay and to elucidate their plausible mechanism of action, a molecular docking study was performed against mycobacterial enoyl-ACP reductase (FabI/ENR/InhA), which is known to play a crucial role in the fatty acids elongation cycle, a step essential for mycolic acid biosynthesis through the mycobacterial type II fatty acid biosynthesis pathway. Mycolic acids are a very long chain of α-alkyl β-hydroxy fatty acids (C74–C90) that form the major component of the mycobacterial cell wall, protecting from antibiotics, and contribute to significantly increasing Mycobacterial virulence. Therefore, inhibition of InhA is shown to be an important strategy to efficiently kill M. tuberculosis under aerobic and anaerobic conditions by blocking the biosynthesis of this vital cell wall component, that is, mycolic acid and consequential cell lysis [21]. For this purpose, the crystal structure of mycobacterial enoyl-ACP reductase (InhA) complexed with its inhibitor was retrieved from the protein data bank (pdb accession code: 4TZK) and subjected to molecular docking study using the standard protocol implemented in the Grid-based Ligand Docking with Energetics module of the Schrödinger Molecular modeling package (Schrödinger, LLC, New York, NY, 2015) to predict the binding modes and affinities of the pyrimidine-5-carbonitriles (6a–6h) [22]. For more details on the protocol adopted for molecular docking, readers are requested to refer to the supplementary material.

The binding modes predicted by the study showed that the pyrimidine-5-carbonitriles (6a–6h) were deeply embedded into the active site of InhA with an excellent binding affinity (Table 1) and engaged in multiple bonded and non-bonded interactions with the residues lining the active site. A detailed per-residue interaction analysis for the most active analog 6f ( Figure 1) showed that molecule could snugly fit into the active site of InhA with a high binding affinity (glide score: −9.387; glide energy: −43.555 kcal/mol), which can be explained in terms of significant network of favorable van der Waals interactions observed with Leu218(−2.002 kcal/mol), Ile215(−2.296 kcal/mol), Leu207(−1.075 kcal/mol), Ile202(−2.214 kcal/mol), Met199(−4.339 kcal/mol), Pro193(−1.228 kcal/mol), Ala191(−1.061 kcal/mol), Lys165(−1.812 kcal/mol), Met161(−2.109 kcal/mol), Tyr158(−3.553 kcal/mol), Ala157(−1.495 kcal/mol), Met155(−1.266 kcal/mol), Phe149(−2.975 kcal/mol), Met147(−1.676 kcal/mol), Met103(−1.948 kcal/mol), and Met98(−1.66 kcal/mol) residues through the 4-amino-2-(3-fluoro-5-(trifluoromethyl) phenyl)pyrimidine-5-carbonitrile scaffold while the 4-cyanophenyl ring was engaged in similar type of interactions with Ala198(−1.593 kcal/mol), Thr196(−3.101 kcal/mol), Phe97(−1.819 kcal/mol), Gly96(−1.459 kcal/mol), Ser20(−1.438 kcal/mol), and Ile16(−1.226 kcal/mol) residues. The higher binding affinity of 6f is also attributed to significant electrostatic interactions with Gly192(−3.683 kcal/mol), Asp148(−1.195 kcal/mol), and Met147(−1.304 kcal/mol) residues. While these non-bonded interactions served as the major driving force for the mechanical interlocking of 6f with InhA, the compound was anchored to the active site through very close hydrogen bonding interactions with Thr17(2.546 Å) and Ser20(2.533 Å) residues via the cyano (–CN) substituent and equally important pi–pi (π–π) stacking interaction observed with Tyr158(2.566 Å) through the fluoro-substituted phenyl ring. A very similar network of bonded and non-bonded interactions was observed for the other pyrimidine-5-carbonitriles in the series which qualifies them as a pertinent starting point for structure-based lead optimization to arrive at molecules with enhanced binding affinity and higher antitubercular potency.

Figure 1 Binding mode of pyrimidine-5-carbonitrile 6f into the active site of mycobacterial enoyl-ACP reductase (InhA).
Figure 1

Binding mode of pyrimidine-5-carbonitrile 6f into the active site of mycobacterial enoyl-ACP reductase (InhA).

4 Conclusion

In summary, we have described the synthesis of pyrimidine-5-carbonitriles adducts as core and were tested for their Mtb H37Rv using effectual and conventional pertinent reaction pathways in three simple step processes. The antimycobacterial screening against M. tuberculosis H37Rv of 6f having CN functionality showed more potency than the other used substituents. The results were supported by molecular docking against InhA and identified as the 6f could provide valuable insight into the plausible mechanism of antitubercular action.

5 Experimental

5.1 Materials

The required chemicals and solvents for the synthesis were purchased from Merck Ltd., SD fine chemicals, LOBA Chemicals, and HIMEDIA. Most of the reactions were carried out by standard techniques for the exclusion of moisture. The open-end capillary method was used to determine the melting points of the synthesized derivatives, and the results were reported and are uncorrected. Thin layer chromatography (TLC) was used for reaction monitoring using ethyl acetate:hexane as mobile phase and visualized in ultraviolet (UV) light (254 and 365 nm). IR spectra of all compounds were recorded on a Bruker FT-IR alpha-t (ATR). “Bruker AVANCE II” spectrometer was used for NMR [(1H: 400 MHz & 13C (101 MHz)] spectra using TMS (internal standard). Mass spectra were recorded on a Shimadzu LC-MS 2010 spectrometer. Elemental analysis was carried out using a Perkin–Elmer 2400 CHN analyzer.

5.2 Method of synthesis

5.2.1 Procedure for the synthesis of 3-fluoro-5-(trifluoromethyl)benzimidamide (2)

In a 100 ml round-bottom flask (RBF, moisture-free), a mixture of methyl-3-fluoro-5-(trifluoromethyl)benzimidothiate (1) (0.01 mol) and ammonium acetate (0.01 mol) in ACN media was allowed to stir for 6 h at room temperature. The completion of the reaction was confirmed by using TLC with mobile phase n-hexane:ethyl acetate (8:2). It was poured onto crushed ice and stirred well for 30 min. The solid separated was filtered and washed with cold water (×3). The product obtained was dried and recrystallized from alcohol. All the targeted derivatives were obtained using the above-stated procedure. The analytically pure product in excellent yield was used for the next step (yield = 88%; mp = 145°C).

The formation of the product was carried out using IR, that is, the primary amine appearing and S-linkage disappearing.

5.2.2 General procedure for the synthesis of substituted 2-benzylidenemalononitrile (5a–h)

The mixture of malononitrile (4) (0.01 mol) and substituted aldehyde (3a–h) (0.01 mol) was charged in RBF and a minute quantity of methanol was used to solubilize the reactants. To this reaction mixture, a catalytic amount of piperidine was added, and it was stirred well for 10 min. The direct solid was separated which was filtered out and washed with methanol to get the pure compound. The completion of the reaction was monitored by TLC using n-hexane:ethyl acetate (6:4) as the mobile phase.

The IR spectrum was used to finalize the product formation (disappear > C═O frequency).

5.2.3 General procedure for the synthesis of 4-amino-2-(3-fluoro-5-(trifluoromethyl)phenyl)-6-arylpyrimidine-5-carbonitrile (6a–6h)

3-Fluoro-5-(trifluoromethyl)benzimidamide (2) (0.01 mol) and 2-benzylidenemalononitriles (5a–h) (0.01 mol) were used to carry out final novel molecules. The mixture of 2 and 5a–5h was refluxed in ACN for 5–6 h in the presence of the catalytic amount of glacial acetic acid. After completion of the reaction (TLC monitored), the solvent was distilled off and the reaction mixture was cooled to RT. The finalized mixture was poured into crushed ice, and the solid separated was filtered and washed with cold water (×3). The product obtained was dried and crystallized from methanol (two times).

All the described scaffolds (6a–6h) were obtained using the above-stated procedure and were confirmed by various spectroscopic techniques.

Compound purity was determined using liquid chromatography coupled to MS with detection by UV absorbance and total ion count from MS. All the analysis was performed after purification of the compounds by column chromatography (Silica 60–120, mobile phase: 20% Ethyl acetate & 80% hexane). LC–MS graph can be found in the Supplementary Material.

5.3 Physical and analytical data

5.3.1 4-Amino-2-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(2-fluorophenyl)pyrimidine-5-carbonitrile (6a)

Purity: 100%; yield: 92%; mp: 188–190°C; IR (cm−1): 3485.37 (N–H stretching primary amine), 3232.70 (C–H, stretching aromatic ring), 2229.71 (C≡N stretching nitriles group), 1635.64 (C═C stretching aromatic ring), 1,541, 1,456, 1,379 (ring skeleton), 1378.12 (C–N stretching C–N linkage in pyrimidine ring), 1226.73 (C–F stretching), 759.95 (aromatic o-disubstitution); 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.53 (s, 1H, Ar-H̲), 8.45 (s, 1H, Ar-H̲), 8.33–8.30 (d, 1H, Ar-H̲), 8.09 (s, 1H, Ar-H̲), 7.98–7.96 (d, 1H, Ar-H̲), 7.77–7.73 (t, 1H, Ar-H̲), 7.70–7.68 (t, 1H, Ar-H̲), 3.35 (s, 2H, primary –NH̲2 group). 13C NMR (101 MHz, DMSO-d6) δ ppm: 170.82, 167.74, 164.73, 162.69, 160.15, 151.07, 143.55, 137.59, 132.45, 129.28, 126.58, 122.98, 121.20, 120.55, 117.68, 115.36, 113.58, 75.52; MS: m/z = 376 (M+); elemental analysis of C18H9F5N4: calculated = C, 57.45; H, 02.41; F, 25.24; N, 14.89; and experimental = C, 57.41; H, 02.44; F, 25.18; N, 14.92.

5.3.2 4-Amino-6-(4-chlorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)pyrimidine-5-carbonitrile (6b)

Purity: 100%; yield: 88%; mp: 144–147°C; IR (cm−1): 3491.16 (N–H stretching primary amine), 3246.62 (C–H stretching aromatic ring), 2222.00 (C≡N stretching nitrile group), 1639.49 (C═C stretching aromatic ring), 1,537, 1,442, 1,379 (ring skeleton), 1359.78 (C–N stretching C–N linkage in pyrimidine ring), 1268.66 (C–F stretching), 839.03 (aromatic p-disubstitution), 804.32 (C–Cl stretching); 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.58 (s, 1H, Ar-H̲), 8.41 (s, 1H, Ar-H̲), 8.11–8.09 (d, 2H, Ar-H̲), 7.59–7.57 (d, 2H, Ar-H̲), 7.28 (s, 1H, Ar-H̲), 5.84 (s, 2H, primary –NH̲2 group). 13C NMR (101 MHz, DMSO-d6) δ ppm: 169.25, 168.45, 164.08, 161.40, 140.41, 138.15, 133.80, 131.63, 131.63, 130.52, 128.75, 128.75, 126.42, 121.01, 118.27, 117.32, 111.57, 73.38; MS: m/z = 392 (M+); elemental analysis of C18H9ClF4N4: calculated = C, 50.05; H, 02.31; F, 19.35; N, 14.27; and experimental = C, 50.10; H, 02.27; F, 19.29; N, 14.34.

5.3.3 4-Amino-6-(4-bromophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)pyrimidine-5-carbonitrile (6c)

Purity: 100%; yield: 87%; mp: 174°C; IR (cm−1): 3482.56 (N–H stretching primary amine), 3234.78 (C–H stretching aromatic ring), 2198.18 (C≡N stretching nitrile group), 1545.18 (C═C stretching aromatic ring), 1,544, 1,458, 1,377 (ring skeleton), 1363.45 (C–N stretching C–N linkage in pyrimidine ring), 1219.18 (C–F stretching), 794.90 (aromatic p-disubstitution), 556.70 (C–Br stretching); 1H NMR (400 MHz, DMSO-d6) δ 8.21 (t, 1H, Ar-H̲, J = 2.2 Hz), 7.65–7.55 (m, 3H, Ar-H̲), 7.54–7.48 (m, 2H, Ar-H̲), 7.47 (m, 1H, Ar-H̲), 6.57–6.47 (s, 2H, primary –NH̲2 group). 13C NMR (101 MHz, DMSO-d6) δ 169.62, 169.60, 166.70, 166.12, 162.90, 162.89, 160.89, 160.87, 138.06, 138.04, 138.00, 137.98, 132.61, 132.05, 131.98, 131.79, 131.73, 131.56, 129.87, 124.03, 123.57, 123.54, 123.25, 123.22, 123.19, 123.18, 123.16, 123.15, 123.13, 121.43, 121.39, 117.03, 117.00, 116.96, 116.93, 116.87, 116.84, 116.80, 116.77, 116.70, 114.44, 114.28, 85.12; MS: m/z = 437 (M+); elemental analysis of C18H9BrF4N4: calculated = C, 49.45; H, 02.07; F, 17.38; N, 12.82; and experimental = C, 49.40; H, 02.11; F, 17.42; N, 12.79.

5.3.4 4-Amino-2-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(4-hydroxyphenyl)pyrimidine-5-carbonitrile (6d)

Purity: 100%; yield: 78%; mp: 166°C; IR (cm−1): 3634.19 (–OH stretching), 3492.22 (N–H stretching primary amine), 3198.19 (C–H stretching aromatic ring), 2224.10 (C≡N stretching nitrile group), 1678.12 (C═C stretching aromatic ring), 1,535, 1,440, 1,376 (ring skeleton), 1384.15 (C–N stretching C–N linkage in pyrimidine ring), 1228.26 (C–F stretching), 837.33 (aromatic p-disubstitution); 1H NMR (400 MHz, DMSO-d6) δ 8.19 (t, 1H, Ar-H̲, J = 2.2 Hz,), 8.04–7.97 (m, 2H, Ar-H̲), 8.02 (s, 1H, –OH̲), 7.61 (m, 1H, Ar-H̲), 7.46 (m, 1H, Ar-H̲), 6.88–6.81 (m, 2H, Ar-H̲), 6.59- 6.51 (s, 2H, primary –NH̲2 group). 13C NMR (101 MHz, DMSO-d6) δ 169.61, 169.59, 166.64, 166.02, 162.80, 162.79, 160.79, 160.77, 158.84, 138.56, 138.55, 138.50, 138.48, 132.19, 132.13, 131.93, 131.87, 130.35, 127.06, 123.56, 123.53, 123.28, 123.20, 123.18, 123.17, 123.15, 123.14, 123.12, 121.42, 121.38, 116.98, 116.96, 116.92, 116.89, 116.83, 116.79, 116.76, 116.73, 116.07, 114.39, 114.23, 85.38; MS: m/z = 374 (M+); elemental analysis of C18H10F4N4O: calculated = C, 57.76; H, 02.69; F, 20.30; N, 14.97; and experimental = C, 57.73; H, 02.72; F, 20.27; N, 14.94.

5.3.5 4-Amino-2-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(4-fluorophenyl)pyrimidine-5-carbonitrile (6e)

Purity: 85%; yield: 75%; mp: 212–214°C; IR (cm−1): 3412.71 (N–H stretching primary amine), 3236.08 (C–H stretching aromatic ring), 2298.18 (C≡N stretching nitrile group), 1631.48 (C═C stretching aromatic ring), 1,540, 1,452, 1,372 (ring skeleton), 1298.81 (C–N stretching C–N linkage in pyrimidine ring), 1231.08 (C–F stretching), 826.90 (aromatic p-disubstitution); 1H NMR (400 MHz, DMSO-d6) δ 8.23 (t, 1H, Ar-H̲, J = 2.2 Hz), 7.64–7.54 (m, 3H, Ar-H̲), 7.46 (m, 1H, Ar-H̲), 7.18–7.10 (m, 2H, Ar-H̲), 6.54–6.47 (s, 2H, primary –NH̲2 group). 13C NMR (101 MHz, DMSO-d6) δ 169.59, 169.58, 166.61, 166.54, 164.80, 162.79, 162.77, 162.74, 160.80, 160.79, 160.71, 160.69, 138.58, 138.55, 138.54, 138.53, 138.51, 138.45, 138.47, 138.46, 132.45, 132.38, 132.20, 132.12, 131.97, 131.86, 131.68, 131.62, 130.41, 130.34, 130.11, 130.08, 125.70, 125.67, 123.54, 123.53, 123.25, 123.22, 123.19, 123.18, 123.16, 123.15, 123.13, 121.42, 121.38, 119.27, 119.24, 116.99, 116.97, 116.93, 116.90, 116.84, 116.80, 116.77, 116.74, 116.15, 115.97, 114.38, 114.25, 85.35; MS: m/z = 376 (M+); elemental analysis of C18H9F5N4: calculated = C, 57.45; H, 02.41; F, 25.24; N, 14.89; and experimental = C, 57.47; H, 02.41; F, 25.21; N, 14.84.

5.3.6 4-Amino-6-(4-cyanophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)pyrimidine-5-carbonitrile (6f)

Purity: 74%; yield: 86%; mp: 178–180°C; IR (cm−1): 3518.31 (N–H stretching primary amine), 3135.17 (C–H stretching aromatic ring), 2215.78 (C≡N stretching nitrile group), 1581.37 (C═C stretching aromatic ring), 1,531, 1,448, 1,384 (ring skeleton), 1338.02 (C–N stretching C–N linkage in pyrimidine ring), 1187.18 (C–F stretching), 831.33 (aromatic p-disubstitution); 1H NMR (400 MHz, DMSO-d6) δ 8.25 (t, 1H, Ar-H̲, J = 2.2 Hz), 7.99–7.93 (m, 2H, Ar-H̲), 7.87–7.80 (m, 2H, Ar-H̲), 7.60 (m, 1H, Ar-H̲), 7.47 (m, 1H, Ar-H̲), 6.51–6.43 (s, 2H, primary –NH̲2 group). 13C NMR (101 MHz, DMSO-d6) δ 169.98, 169.78, 166.61, 166.58, 162.91, 162.89, 160.89, 160.88, 138.53, 138.51, 138.46, 138.45, 135.34, 132.83, 132.18, 132.12, 131.92, 131.84, 129.31, 123.57, 123.52, 123.24, 123.21, 123.18, 123.28, 123.25, 123.24, 123.22, 121.43, 121.39, 118.48, 116.84, 116.81, 116.78, 116.75, 116.68, 116.65, 116.62, 116.59, 114.22, 114.29, 112.46, 85.12; MS: m/z = 383 (M+); elemental analysis of C19H9F4N5: calculated = C, 59.54; H, 02.37; F, 19.83; N, 18.27; and experimental = C, 59.50; H, 02.35; F, 19.86; N, 18.29.

5.3.7 4-Amino-6-(4-(dimethylamino)phenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)pyrimidine-5-carbonitrile (6g)

Purity: 100%; yield: 76%; mp: 209°C; IR (cm−1): 3488.64 (N–H stretching primary amine), 3010.31 (C–H stretching aromatic ring), 2178.22 (C≡N stretching nitrile group), 1638.88 (C═C stretching aromatic ring), 1,538, 1,449, 1,381 (ring skeleton), 1362.73 (C–N stretching C–N linkage in pyrimidine ring), 1225.70 (C–F stretching), 762.94 (aromatic o-disubstitution); 1H NMR (400 MHz, DMSO-d6) δ 8.18 (t, 1H, Ar-H̲, J = 2.2 Hz), 7.62 (m, 1H, Ar-H̲), 7.58–7.52 (m, 2H, Ar-H̲), 7.46 (m, 1H, Ar-H̲), 6.78–6.72 (m, 2H, Ar-H̲), 6.57 (s, 2H, primary –NH̲2 group), 3.00 (s, 6H, –CH̲3). 13C NMR (101 MHz, DMSO-d6) δ 169.22, 169.20, 166.78, 165.79, 162.70, 151.99, 138.48, 138.36, 138.30, 129.49, 127.24, 123.29, 123.22, 123.17, 123.12, 116.84, 116.69, 116.40, 116.26, 116.13, 114.59, 114.55, 111.60, 85.42, 40.12; MS: m/z = 401 (M+); elemental analysis of C20H15F4N5: calculated = C, 59.85; H, 03.77; F, 18.93; N, 17.45; and experimental = C, 59.81; H, 03.81; F, 18.88; N, 17.48.

5.3.8 4-Amino-2-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(3,4-dimethoxyphenyl)pyrimidine-5-carbonitrile (6h)

Purity: 100%; yield: 76%; mp: 186–188°C; IR (cm−1): 3510.68 (N–H stretching primary amine), 3295.18 (C–H stretching aromatic ring), 2224.38 (C≡N stretching nitrile group), 1589.75 (C═C stretching aromatic ring), 1,539, 1,441, 1,377 (ring skeleton), 1378.91 (C–N stretching C–N linkage in pyrimidine ring), 1168.31 (C–F stretching), 1216.06 (C-O stretching –OCH3 group), 820.30 (aromatic p-disubstitution); 1H NMR (400 MHz, DMSO-d6) δ 8.22 (t, 1H, Ar-H̲, J = 2.1 Hz), 7.61 (m, 1H, Ar-H̲), 7.49–7.38 (m, 2H, Ar-H̲), 7.35 (d, 1H, Ar-H̲, J = 1.7 Hz,), 7.18 (d, 1H, Ar-H̲, J = 8.4 Hz,), 6.39–6.06 (s, 2H, primary –NH̲2 group), 3.87 (s, 6H, –CH̲3). 13C NMR (101 MHz, DMSO-d6) δ 169.42, 169.40, 166.46, 165.43, 162.91, 162.90, 160.99, 160.97, 151.34, 149.33, 138.88, 138.86, 138.81, 138.80, 132.24, 131.88, 131.92, 131.82, 128.11, 123.41, 123.38, 123.32, 123.28, 123.27, 123.25, 123.23, 123.20, 121.57, 121.53, 116.99, 116.95, 116.92, 116.89, 116.86, 116.79, 116.76, 116.53, 116.50, 114.25, 114.09, 113.21, 112.14, 83.85, 56.18, 55.93; MS: m/z = 418 (M+); elemental analysis of C20H14F4N4O2: calculated = C, 57.42; H, 03.37; F, 18.17; N, 13.39; and experimental = C, 57.45; H, 03.35; F, 18.22; N, 13.41.

5.4 Microbiology

The antimicrobial activity (M. tuberculosis H37Rv; aerobic conditions) of compounds 6a–6h was evaluated as a part of the contract number HHSN272201100009I/HHSN27200002 A14 with the NIAID division, USA, and the Saurashtra University, Rajkot. All methods and conditions (protocols) used to carry out the antimycobacterial of the derived adducts are provided in the supplementary file.

tel: +91 9586980779

Acknowledgments

The authors are thankful to the Saurashtra University, Rajkot & School of Science, RK University, Rajkot, for their great support in laboratory and library facilities. They are also thankful to CoE, NFDD Centre for instrumental support, and Schrödinger Inc. for providing GLIDE software to carry out the molecular docking studies. Special thanks to NIAID, USA, for their antitubercular studies.

  1. Funding information: Authors state no funding involved.

  2. Conflict of interest: Authors state no conflict of interest.

  3. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2021-09-25
Revised: 2021-12-14
Accepted: 2022-01-12
Published Online: 2022-06-15

© 2022 Khushal M. Kapadiya et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/hc-2022-0010
Keywords for this article
pyrimidine-5-carbonitriles; antitubercular activity; trifluoro functionality; molecular docking
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