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Rasayan J. Chem., 16(1), 527-535(2023)
http://doi.org/10.31788/RJC.2023.1618008
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SYNTHESIS AND EVALUATION OF SOME NEW
SUBSTITUTED PIPERAZINYL-ARYL AMIDE, ACETAMIDE,
AND SULFONAMIDE DERIVATIVES OF ROSUVASTATIN
INTERMEDIATE AND THEIR ANTI-MICROBIAL ACTIVITY
Donka Suresh Babu1, Doddaga Srinivasulu1,, Valaparla Bala Yesu1,
V.V.P.C. Narayana1, Murali Vatturu1, Sajitha Kethineni1 and Meriga Balaji2
1Department of Chemistry, Sri Venkateswara University, Tirupati-517502 (A. P.) India
2Department of Biochemistry, Sri Venkateswara University, Tirupati-517502 (A. P.) India
Corresponding Author: doddaga_s@yahoo.com
ABSTRACT
In pursuit of a biodynamically potent molecule, we have attempted to synthesize derivatives of piperazine by
incorporating them into the Rosuvastatin intermediate. The reason behind this is that heterocyclic compounds with
nitrogen atoms in their ring structure, such as pyrimidine, have great potential as drug design scaffolds. By doping
piperazine into the Rosuvastatin intermediate, a series of new derivatives made up of aryl-amides, acetamides, and
sulfonamides were produced. These derivatives were then assessed for their antimicrobial activity, with a few
showing promising results.
Keywords: Rosuvastatin Intermediate, Piperazine, Amide, Anti-microbial activity.
RASĀYAN J. Chem., Vol. 16, No.1, 2023
INTRODUCTION
Heterocycles containing pyrimidine moieties are found to possess antimicrobial1,2,3,4,5, antileishmanial6,
antiinflammatory7, analgesic8, antihypertensive9, antipyretic10, antiviral11, antidiabetic12, antiallergic13,
anticonvulsant14, antioxidant15,16, antihistaminic17, and anticancer activities.18,19 Besides, pyrimidine along
with piperazine containing heterocyclic compounds possesses more potent biological assays and acts as
an effective antimicrobial agent. Piperazine derivatives are important pharmacophores in chemotherapy as
well as important building blocks of biologically active molecule construction. In the piperazine ring,
nitrogen atoms enhance favorable interaction with biomacromolecules hence explored for several
biological activities.20,21 Sulfonamide drugs are an important group of organic compounds that hold
several types of biological activities.22,23 Rosuvastatin24 is a statin-class drug, used to treat high
cholesterol, and cardiovascular disease, and is stated to be antimicrobial in nature.25 For the enhancement
of antimicrobial activity, piperazine derivatives are incorporated into the structure of Rosuvastatin and its
modified intermediate shown in Fig.-1.
Fig.-1: Rosuvastatin and incorporated Piperazine-Rosuvastatin analogs
In light of the above-aforementioned outlines, we have been attentive to the design and synthesis of novel
pyrimidine-containing Rosuvastatin derivatives. Furtherly, piperazine moiety was incorporated to
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enhance its biological activity. So, herein we reported the synthesis and screened for antimicrobial
activity of piperazine Rosuvastatin pyrimidine derivatives.
EXPERIMENTAL
Chemical Materials and Apparatus
Aromatic acids, phenylacetic acids, benzene sulfonyl chlorides, and all chemicals, and solvents were
utilized after being obtained from merk, TCI, and AVRA. Melting points of respective final derivatives
determined in exposed capillaries on GUNA, and were uncorrected, 1HNMR and 13CNMR bands
executed on Bruker 400 MHz, the FT-IR spectrum was performed on JASCO IR 5300 using KBR pallets,
and the LC-Mass spectra were noted on API 3000 mass spectrometer.
Biological Materials and Apparatus
All chemicals, buffer solutions, and agarose gel were purchased from Thermo Fischer Scientific and
Sigma Aldrich. Electrophoresis was performed in agarose gels with 4% Tris-Borate-EDTA (TBE).
Fluorescence emissions were screened and quantified by double fluorescence FMYG100 microscope.
Cytofluorometric analysis was noted on Beckman Coulter’s Gallio’s 10/3 Cytofluorometer.
Chemistry
The designed new series of aryl amide, acetamide, and sulfonamide derivatives of piperazine-rosuvastatin
hybrid final Compounds 3(a-d), 4(a-d), and 5(a-h) have been illustrated as outlined in Fig.-2. Initially, the
piperazine intermediate (2), was obtained from the starting compound (1) with piperazine, the presence of
K2CO3 in 1,4-dioxane at 80 °C. Furtherly, piperazine intermediate (2), was treated with several
substituted benzoic acids, and phenylacetic acids, using triethylamine, EDC, and HOBT, to afford titled
compounds 3 (a-d) and 4 (a-d) in good yields. Besides, piperazine intermediate (2) was treated with
several aromatic sulphonyl chlorides with TEA in DCM to get compounds 5 (a-h) with high yields. All
the derivatives were characterized through 1HNMR, 13CNMR, IR, and Mass spectral analysis in the
experimental section.
Fig.-2
Synthesis of the compound (2)
Piperazine (1.2 eq), potassium carbonate (2.5 eq), and compound-1 (1 eq) were all gently dissolved in
1,4-dioxane. The above reaction refluxed for 2-3 hours at 80-90 °C. After chilling, added cold water,
extracted by 10% methanol in DCM, collective-organic layers were dehydrated with Na2SO4, sieved, and
concentrated under vacuum pressure, the reaction product was purified through column-chromatography
at 5-10% methanol in dichloromethane as eluent, and the compound (2) was obtained. Yield: 3.2 g (79%),
M.P- 121-123 °C, 1H-NMR (400 MHz, CDCl3): δH 7.608-7.512 (m, 2H), δH 7.136-7.071 (m, 2H), δH
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ROSUVASTATIN SUBSTITUTED PIPERAZINYL-ARYL AMIDE Donka Suresh Babu et al.
3.952 (s, 2H), δH 3.511-3.392 (m, 7H), δH 2.954-2.772 (m, 4H), δH2.431-2.192 (m, 4H), δH 1.264 (d,
6H), (+)ESI-MS m/z: calculated for [C20H28FN5O2S + H+] 421.54, observed 422.6.
Scheme-1: Synthesis of Aryl Amide, Acetamide, and Sulfonamide derivatives of Piperazinyl Rosuvastatin
Intermediate 3(a-d), 4(a-d), and 5(a-h)
General Procedure of the Compounds 3(a-d) and 4(a-d)
Compound-2 (1 eq) in DMF (10 mL), then added triethylamine (3 eq), EDC (2.5 eq), and HOBT (2.5 eq).
successively, followed by the addition of substituted phenyl acids and phenylacetic acids (1.5 eq), the
above reaction was agitated at ambient temperature for 12-13 hours under nitrogen, the reaction was
quenched through saturated NaHCO3 solution, added water, EtOAc was used to extract the product,
splashed with brine solution, separated organic layer dehydrated with Na2SO4, sieved, and concentrated,
acquired crude was refined by column-chromatography at 40-60% EtOAc-Hexane as eluent to get
compounds 3(a-d), and 4(a-d) with admirable yields.
Analytical Data for 3 (a-d) and 4 (a-d)
3a: N-(5-(4-(cyclopropanecarbonyl-piperazin-1-ylmethyl)-4-(4-Fluoro-Phenyl)-6-Iso-Propyl-pyrimidin-2-
yl)-N-Methyl-Methanesulfonamide. Pale-yellow solid, M.P- 131-133 °C, Yield (74%). FT-IR(KBr, cm-1):
2933, 1735, 1620, 1543, 1338, 1243, 1140, 961, 773, 1H-NMR (400 MHz, CDCl3): δH 7.572-7.537 (m,
2H,), δH 7.133 (t, 2H), δH 3.556-3.514 (m, 13H), δH 2.263 (bs, 4H), δH 1.313 (d, 6H), δH 1.297-1.184
(m, 1H), δH ,0.953-0.915 (m, 2H), δH 0.740-0.694 (m, 2H); 13C-NMR (CDCl3): δC 177.9, δC 167.0, δC
164.5, δC 162.1, δC 134.8, δC 131.4, δC 119.1, δC 115.4, δC 115.2, δC 53.7, δC 42.6, δC 33.2, δC 31.9,
δC 22.3, δC 10.9, δC 7.55, (+)ESI-MS m/z: calculated for [C12H32FN6O3S + H+] 489.61, observed 490.1
3b: N-(-4-(4-Fluoro-Phenyl)-6-Iso-Propyl-5-(-4-picolinoylpiperazin-1-ylmethyl)-pyrimidin-2-yl)-N-
Methyl-Methanesulfonamide. Off white solid, M.P-185-187 oC, Yield (70%). FT-IR (KBr, cm-1): 2931,
1730, 1629, 1546, 1337, 1224, 1151, 960, 771, 1H-NMR (400 MHz, CDCl3): δH 8.652-8.596 ( m, 2H),
δH 7.715-7.686 ( m, 1H), δH 7.544-7.509 (m, 2H), δH 7.359-7.327 (,m, 1H), δH 7.164-7.121 (,m, 2H),
δH 3.682-3.327 (,m, 13H), δH 2.421-2.196 (m, 4H), δH 1.308 (d, 6H); 13CNMR (100.6 MHz, CDCl3,
δC): δC 177.9, δC 167.7, δC 167.1, δC 164.5, δC 157.8, δC 151.0, δC 148.0, δC 135.3, δC 134.5, δC
124.2, δC 123.5, δC 118.9, δC 115.5, δC 115.3, δC 53.7, δC 42.7, δC 33.2, δC 31.9, δC 22.3, (+)ESI-MS
m/z: calculated for [C26H31FN6O3S + H+] 526.63, observed 527.1
3c: N-(5-(4-2-chlorobenzoyl-piperazin-1-ylmethyl)-4-(-4-Fluoro-phenyl)-6-Iso-Propyl-Pyrimidin-2-yl)-
N-Methyl-Methanesulfonamide. Off white solid, M.P- 105-107 °C, Yield (77%). FT-IR (KBr cm-1): 2929,
1735, 1637, 1544, 1342, 1224, 1151, 960, 769, 1H-NMR (400 MHz, CDCl3): δH 9.404-9.323 (m, 1H), δH
8.579 (d, 2H), δ H7.843 (d, 1H), δH 7.558-7.536 (m, 3H). δH 7.164 (d, 2H), δH 3.785 (s, 2H), δH 3.566-
3.516 (m, 11H), δH 2.400-2.286 (m, 4H), δH 1.324 (d, 6H), 13C-NMR (CDCl3):- δC 177.9, δC 167.0, δC
165.2, δC 162.2, δC 158.7, δC 157.7, δC 144.1, δC 143.8, δC 132.3, δC 131.3, δC 124.6, δC 118.7, δC
115.4, δC 115.2, δC 53.6, δC 52.5, δC 51.8, δC 47.2, δC 42.6, δC 33.1, δC 31.9, δC 22.2; (+)-ESI-MS
m/z: calculated for [C27H31ClFN5O3S + H+] 560.08, observed 561.0.
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ROSUVASTATIN SUBSTITUTED PIPERAZINYL-ARYL AMIDE Donka Suresh Babu et al.
3d: N-(-4-(-4-Fluoro-Phenyl)-6-Iso-Propyl-5-(-4-5-nitropicolinoyl-Piperazin-1-ylMethyl)-Pyrimidin-2-
yl)-N-Methyl-methanesulfonamide. Off-White solid, M.P- 221-223 °C, Yield (75%). FT-IR (KBr, cm-1):
2930, 1734, 1632, 1545, 1340, 1232, 1149, 960, 772; 1H-NMR ( 400 MHz, CDCl3): δH 7.560-7.530 ( m,
2H), δH 7.525-7.388 (,m, 1H), δH 7.383-7.305 (m, 1H), δH 7.231-7.208 (m, 1H), δH 7.136 (t, 2H), δH
3.696 (s, 2H), δH 3.544-3.092 (m, 11H), δH 2.385-2.269 (m, 4H), δH 1.309 (d, 6H), 13C-NMR (CDCl3):
δC 177.9, δC 167.1, δC 166.8, δC 164.6, δC 162.1, δC 157.8, δC 135.9, δC 134.6, δC 131.4, δC 130.4, δC
127.9, δC 119.0, δC 115.4, δC 115.2, δC 53.7, δC 52.6, δC 51.9, δC 46.8, δC 42.6, δC 41.8, δC 33.2, δC
31.9, δC 22.3, (+)ESI-MS m/z: calculated for [C26H30FN7O5S + H+] 571.62, observed 572.2.
4a: N-(-4-(-4-Fluoro-Phenyl)-6-Iso-Propyl-5-(4-(-2-4,trifluoromethyl-phenyl-acetyl)-Piperazin-1-yl-
Methyl)pyrimidin-2-yl)-N-Methyl-Methanesulfonamide. White solid, M.P- 138-140 °C, Yield (80%). FT-
IR (KBr, cm-1): 2970, 1735, 1643, 1546, 1313, 1226, 1153, 962, 769, 1H-NMR ( 400 MHz, CDCl3): δH
7.645 ( d, 1H), δH 7.549-7.460 (m, 3H), δH 7.372-7.292 (m, 2H), δH 7.136 (t, 2H), δH 3.810 (s, 2H), δH
3.542-3.291 (m, 11H), δH 3.311 (t, 2H), δH 2.274-2.156 (m, 4H), δH 1.303 (d, 6H), 13C-NMR (CDCl3):
δC 177.9, δC 167.0, δC 165.2, δC 162.2, δC 158.7, δC 157.7, δC 144.1, δC 143.8, δC 132.3, δC 131.3, δC
124.8, δC 118.9, δC 115.4, δC 115.2, δC 53.6, δC 52.5, δC 51.8, δC 47.2, δC 42.6, δC 33.1, δC 31.9, δC
22.3, (+)ESI-MS m/z: calculated for [C29H33F4N5O3S + H+] 607.66, observed 608.2.
4b: N-(-4-(-4-Fluoro-Phenyl)-6-Iso-Propyl-5-(,4-(-2-4-methoxyphenyl-acetyl)-piperazin-1-
ylMethyl)Pyrimidin-2-yl)-N-Methyl-Methanesulfonamide. Off white solid, M.P- 118-120 °C,
Yield (76%). FT-IR (KBr, cm-1):- 2953, 1734, 1637, 1543, 1336, 1230, 1151, 964, 771, 1H-NMR (400
MHz, CDCl3): δH 7.533-7.498 (m, 2H), δH 7.145-7.088 (m, 4H), δH 6.834 (d, 2H), δH 3.782 (s, 3H), δH
3.603 (s, 2H), δH 3.552-3.446 (m, 11H), δH 3.316 (t, 2H), δH 2.238-2.049 (m, 4H), δH 1.283 (d, 6H),
13C-NMR (CDCl3): δC 177.9, δC 169.7, δC 167.1, δC 164.5, δC 162.2, δC 158.5, δC 131.4, δC 131.3, δC
129.7, δC 127.0, δC 119.0, δC 115.4, δC 115.2, δC 114.2, δC 55.3, δC 53.6, δC 52.2, δC 52.1, δC 46.4,
δC 42.5, δC 41.9, δC 40.1, δC 33.2, δC 31.8, δC 22.6; (+)ESI-MS m/z: calculated for [C29H33F4N5O3S +
H+] 569.69, observed 571.2.
4c: N-(-5-(-4-(2-4-cyanophenyl-acetyl)piperazin-1-ylMethyl)-4-(4-Fluoro-phenyl)-6-Iso-Propyl-
Pyrimidin-2-yl)-N-Methyl-Methanesulfonamide. Off white solid, M.P-141-143 °C, Yield (73%). FT-IR
(KBr, cm-1): 2931, 1755, 1606, 1546, 1332, 1224, 1149, 962, 773; 1H-NMR (400 MHz, CDCl3): δH 7.602
(d, 2H), δH 7.539-7.504 (m, 2H), δH 7.314 (d, 2H), δH 7.138 (t, 2H), δH 3.702 (s, 2H), δH 3.545-3.412
(m, 11H), δH 3.318 (s, 2H), δH 2.466-2.132 (m, 4H), δH 1.296 (d, 6H), 13C-NMR (CDCl3): δC 177.8, δC
168.7, δC 167.1, δC 162.0, δC 157.8, δC 140.5, δC 134.8, δC 132.4, δC 131.4, δC 131.3, δC 129.9, δC
118.8, δC 115.4, δC 115.2, δC 111.0, δC 53.6, δC 52.3, δC 52.0, δC 46.1, δC 42.6, δC 42.0, δC 40.5, δC
33.2, δC 31.9, δC 22.5, (+)ESI-MS m/z: calculated for [C29H33F4N5O3S + H+] 564.67, observed 565.6.
4d: N-(-4-(-4-Fluoro-Phenyl)-6-Iso-Propyl-5-(-4-(-2-4-nitrophenyl-acetyl)-piperazin-1-ylMethyl)-
pyrimidin-2-yl)-N-Methyl-Methanesulfonamide. Off-white solid, M.P- 162-164 °C, Yield (72%). FT-IR
(KBr, cm-1): 2956, 1735, 1647, 1541, 1338, 1228, 1151, 947, 771, 1H-NMR (400 MHz, CDCl3): δH 8.168
(d, 2H), δH 7.534-7.499 (m, 2H), δH 7.372 (d, 2H), δH 7.129 (t, 2H), δH 3.747 (s, 2H), δH 3.545-3.412
(m, 11H), δH 3.335-3.325 (m, 2H), δH 2.263-2.147 (m, 4H), δH 1.294 (d, 6H); 13C-NMR (CDCl3): δC
177.8, δC 167.9, δC 167.2, δC 162.1, δC 157.8, δC 147.1, δC 142.6, δC 131.4, δC 131.3, δC 130.0, δC
123.9, δC 118.9, δC 115.4, δC 115.2, δC 53.6, δC 52.3, δC 52.0, δC 46.2, δC 42.6, δC 42.1, δC 40.2, δC
33.3, δC 31.9, δC 22.4, (+)ESI-MS m/z: calculated for [C28H33FN6O5S + H+] 584.66, observed 585.1.
General Procedure of the Compounds 5(a-h)
At 0 °C, Compound-2 (1 eq) in DCM, treated with substituted benzene sulfonyl chlorides (1.5 eq) was
used in combination with triethylamine (3.0 eq). In a nitrogen environment, the reaction mixture was
agitated for three hours at ambient temperature. Following the completion of the reaction, water was
added and the residue was extracted with DCM. The collective organic layer, washed with water and
brine solution, dehydrated over anhydrous Na2SO4, sieved, and concentrated. The acquired crude was
purified by column chromatography at 40-60% ethylacetate-hexane as an eluent to get compounds 5(a-h)
in good yields.
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Analytical Data for 5(a-h)
5a:N-(4-(-4-Fluoro-Phenyl)-6-Iso-Propyl-5-(-4(-4-Methyl-sulfonyl-benzenesulfonyl)-Piperazin-1-
ylMethyl)-Pyrimidin-2-yl)-N-Methyl-Methanesulfonamide. Off-White solid, M.P-116-118 °C, Yield
(84%). FT-IR (KBr, cm-1): 2964, 1604, 1546, 1315, 1226, 1151, 956, 746, 1H-NMR (400 MHz, CDCl3):
δH 8.113 (d, 2H), δH 7.904 (d, 2H), δH 7.498-7.463 (m, 2H), δH 7.131-7.088 (m, 2H), δH 3.526-3.486
(m, 8H), δH 3.417-3.298 (m, 1H), δH 3.108 (s, 3H), δH 2.947 (bs, 4H), δH 2.346 (bs, 4H), δH 1.227 (d,
6H), 13C-NMR (CDCl3): δC 177.8, δC 167.0, δC 159.1, δC 144.61, δ, C 131.4, δC 131.2, δC 128.6, δC
128.4, δC 115.6, δC 115.3, δC 53.3, δC 51.5, δC 46.0, δC 44.4, δC 42.7, δC 33.2, δC 31.8, δC 31.7, δC
22.3, (+)ESI-MS m/z: calculated for [C27H34FN5O6S3 + H+] 639.78, observed 640.2.
5b: N-(-5-(-4-2,4-difluoro-benzenesulfonyl-piperazin-1-ylmethyl-)-4-(-4-Fluoro-Phenyl)-6-Iso-Propyl-
Pyrimidin-2-yl)-N-Methyl-Methanesulfonamide. White-solid, M.P- 144-146 °C, Yield (85%). FT-IR
(KBr, cm-1): 2852, 1598, 1541, 1361, 1217, 1145, 948, 769, 1H-NMR (400 MHz, CDCl3): δH 7.843-
7.7802 (m, 1H), δH 7.524-7.489 (m, 2H), δH 7.119 (t, 2H), δH 7.017-6.929 (m, 2H), δH 3.534-3.495 (m,
8H), δH 3.416-3.309 (m, 1H), δH 3.074 (bs, 4H), δH 2.340 (bs, 4H), δH 1.258 (d, 6H), 13C-NMR
(CDCl3): δC 177.8, δC 167.1, δC 165.1, δC 162.6, δC 157.2, δC 133.0, δC 131.4, δ, C 131.5, δC 122.2,
δC 115.3, δC 115.2, δC 112.2, δC 112.0, δC 105.9, δC 53.4, δC 51.8, δC 42.6, δC 33.2, δC 31.8, δC 31.7,
δC 22.3, (+)ESI-MS m/z: calculated for [C26H30F3N5O4S2 + H+] 597.67, observed 598.5.
5c: N-(5-(-4-(3-chloro-4-fluoro-benzenesulfonyl)-piperazin-1-ylmethyl)-4-(-4-Fluoro-Phenyl)-6-Iso-
Propyl-Pyrimidin-2-yl)-N-Methyl-Methanesulfonamide. Off white solid, M.P-148-150 °C, Yield (79%).
FT-IR (KBr, cm-1): 2974, 1604, 1543, 1350, 1226, 1153, 943, 734, 1H-NMR( 400 MHz, CDCl3): δ,H
7.779 (d, 1H), δH 7.596-7.474 (m, 3H), δH 7.313 (d, 1H), δH 7.141 (d, 2H), δH 3.712-3.486 (m, 8H), δH
3.489-3.312 (m, 1H), δH 2.985 (bs, 4H), δH 2.397 (bs, 4H), δH 1.252 (d, 6H), 13C-NMR (CDCl3): δC
177.1, δC 167.3, δC 165.4, δC 162.5, δC 133.1, δC 131.3, δC 131.4, δC 130.9, δC 128.7, δC 128.2, δC
128.0, δC 117.8, δC 117.5, δC 115.8, δC 54.1, δC 51.4, δC 42.6, δC 33.2, δC 22.31, (+)ESI-MS m/z:
calculated for [C26H30ClF2N5O4S2 + H+] 614.13, observed 615.2.
5d: N-(-4-(-4-Fluoro-Phenyl)-6-Iso-Propyl-5-(-4-4-methoxy-benzeneSulfonyl-piperazin-1-yl-Methyl)-
Pyrimidin-2-yl)-N-Methyl-Methanesulfonamide. White solid, M.P- 160-162 °C, Yield (82%). FT-IR
(KBr, cm-1): 2958, 1593, 1543, 1330, 1226, 1149, 960, 736, 1H-NMR (400 MHz, CDCl3): δH 7.646 (d,
2H), δH 7.505-7.471 (m, 2H), δH 7.086 (t, 2H), δH 6.994 (d, 2H), δH 3.875 (s, 3H), δH 3.589-3.421 (m,
8H), δH 3.381-3.316 (m, 1H), δH 2.862 (bs, 4H), δH 2.330 (bs, 4H), δH 1.223 (d, 6H), 13C-NMR
(CDCl3): δC 177.8, δC 167.2, δC 163.2, δC 162.0, δC 157.7, δC 134.8, δC 131.3, δC 131.2, δC 129.9, δC
127.41, δC 118.9, δC 115.4, δC 115.1, δC 114.3, δC 55.7, δC 53.2, δC 51.5, 46.1, δC 42.6, δC 33.2, δC
31.7, δC 22.2; (+)ESI-MS m/z: calculated for [C27H34FN5O5S2 + H+] 591.72, observed 592.2.
5e: N-(-5-(-4-cyclopropylsulfonyl-Piperazin-1-yl-Methyl)-4-(-4-Fluoro-Phenyl)-6-Iso-Propyl-Pyrimidin-
2-yl)-N-Methyl-Methanesulfonamide. Off white solid, M.P- 174-176 °C, Yield (75%). FT-IR(KBr, cm-1):
2850, 1604, 1552, 1327, 1296, 1153, 958, 744, 1H-NMR (400 MHz, CDCl3): δH 7.561-7.526 (m, 2H), δH
7.162-7.119 (m, 2H), δH 3.625-3.504 (m, 8H), δH 3.475-3.409 (m, 1H), δH 3.178 (bs, 4H), δH 2.362 (bs,
4H), δH 2.239-2.215 (m, 1H), δH 1.308 (d, 6H), δH 1.145-1.105 (m, 2H), δH 0.985-0.936 (m, 2H), 13C-
NMR (CDCl3): δC 177.8, δC 167.1, δC 162.1, δC 157.8, δC 134.7, δ, C 131.4, δC 131.3, δC 118.9, δC
115.7, δC 115.2, δC 53.6, δC 51.9, δC 46.3, δC 42.7, δC 33.2, δC 31.9, δC 25.7, δC 22.3, (+)ESI-MS m/z:
calculated for [C23H32FN5O4S2 + H+] 525.66, observed 526.2.
5f: N-(5-(-4-3,5-Dimethylisoxazol-4-yl-sulfonyl-piperazin-1-yl-Methyl)-4-(4-Fluoro-Phenyl)-6-Iso-
Propyl-Pyrimidin-2-yl)-N-Methyl-Methanesulfonamide. Off white solid, M.P-207-209 °C, Yield (76%).
FT-IR (KBr, cm-1): 2976, 1587, 1543, 1330, 1222, 1151, 943, 734, 1H-NMR (400 MHz, CDCl3): δH
7.694-7.352 (m, 2H), δH 7.260-6.984 (m, 2H), δH 3.795-3.224 (m, 9H), δH 2.992 (bs, 4H), δH 2.598 (bs,
4H), δH 2.357 (s, 6H), δH 1.271 (d, 6H), 13C-NMR (CDCl3): δC 177.8, δC 173.9, δC 167.1, δC 164.6, δC
162.1, δC 158.1, δC 134.7, δ, C 131.1, δC 131.2, δC 118.6, δC 115.5, δC 115.3, δC 113.3, δC 53.3, δC
51.5, δC 45.8, δC 42.7, δC 33.2, δC 31.8, δC 22.3, δC 13.0, δC 11.4, (+)ESI-MS m/z: calculated for
[C25H33FN6O5S2 + H+] 580.70, observed 581.2.
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ROSUVASTATIN SUBSTITUTED PIPERAZINYL-ARYL AMIDE Donka Suresh Babu et al.
5g: N-(-5-(-4-3,4-Dimethoxy-benzenesulfonyl-Piperazin-1-yl-methyl)-4-(-4-Fluoro-Phenyl)-6-Iso-Propyl-
Pyrimidin-2-yl)-N-Methyl-Methanesulfonamide. Off white solid, M.P-198-200 °C, Yield (81%). FT-IR
(KBr, cm-1): 2980, 1589, 1543, 1338, 1267, 1153, 948, 732, 1H-NMR (400 MHz, CDCl3):- δH 7.501-
7.468 (m, 2H), δ, H 7.321 (d, 1H), δH 7.145-7.070 (m, 3H), δ, H 6.956 (d, 1H), δH 3.945 (d, 6H), δH
3.584-3.423 (m, 8H), δH 3.380-3.316 (m, 1H), δH 2.879 (bs, 4H), δH 2.329 (bs, 4H), δH 1.225 (d, 6H),
13C-NMR (CDCl3): δC 177.7, δC 167.0, δC 164.5, δC 162.0, δC 152.8, δC 149.1, δC 134.7, δC 131.3, δC
131.2, δC 127.5, δC 121.7, δC 118.9, δC 115.4, δC 115.2, δC 110.7, δC 56.3, δC 53.3, δC 51.5, δC 46.1,
δC 42.6, δC 33.1, δC 31.7, δC 22.22; (+)ESI-MS m/z: calculated for [C28H36FN5O6S2 + H+] 621.74,
observed 622.2.
5h: N-(5-(-4-2,5-Dimethyl-benzenesulfonylpiperazin-1-ylMethyl)-4-(-4-Fluoro-phenyl)-6-Iso-Propyl-
Pyrimidin-2-yl)-N-Methyl-Methanesulfonamide. (5h): Off white solid, M.P-168-170 °C; Yield (80%).
FT-IR (KBr, cm-1): 2937, 1602, 1544, 1338, 1226, 1151, 941, 732, 1H-NMR (400 MHz, CDCl3): δH
7.669 (s, 1H), δH 7.516 (t, 2H),δH 7.260 (d, 1H), δH 7.185 (d, 1H), δH 7.133-7.092 (m, 2H), δH 3.582-
3.515 (m, 8H), δH 3.429-3.380 (m, 1H), δH 3.051 (bs, 4H),δH 2.519 (s, 3H), δH 2.355 (s, 3H), δH 2.306
(bs, 4H), δH 1.268 (d, 6H), 13C-NMR (CDCl3): δC 177.8, δC 167.1, δC 162.4, δC 157.7, δC 136.1, δC
135.2, δC 134.9, δC 133.8, δC 132.8, δC 131.4, δC 131.3, δC 130.8, δC 118.9, δC 115.4, δC 115.2, δC
53.5, δC 51.8, δC 45.3, δC 42.6, δC 33.2, δC 31.8, δC 22.3, δC 20.9, δC 20.33, (+)ESI-MS m/z:
calculated for [C28H36FN5O4S2 + H+] 589.74, observed 590.2
Biological Activity
The antibacterial activity of synthesized compounds 3(a-d), 4(a-d), and 5(a-h) was assessed against one
strain of Gram-negative (Escherichia coli) and two strains of Gram-positive (Staphylococcus aureus and
Lactobacillus acidophilus) bacteria strains using the agar well diffusion method.26,27 The antibacterial
activity results were measured as the diameter of the inhibition zone, and streptomycin as a standard drug.
Titled Compounds 3(a-d), 4(a-d), and 5(a-h) were screened against four fungal strains, namely the
Clostridium tetani, Aspergillus niger, Aspergillus fumigatus, and Trichoderma harzianum using the agar
disc diffusion method28. The antifungal activity results are expressed in the diameter of the inhibition
zone, and Nystatin is a standard drug.
RESULTS AND DISCUSSION
Chemistry
A series of new Rosuvastatin-piperazine derivatives of aryl amide, acetamide, and sulfonamide were
synthesized by compound (1) with piperazine in presence of K2CO3 in 1,4-dioxane to afford compound
(2). Subsequently, the substituted phenyl acids and phenylacetic acids are allowed to react with compound
2 in DMF by using amide coupling agents, to afford titled compounds 3 (a-d) and 4 (a-d) in good yields
(70-80%). Further, compound 2 was treated with aromatic sulfonyl chlorides in DCM to get compound 5
(a-h) in high yields. Titled derivatives were characterized by FT-IR, 1H and 13C NMR and mass spectra.
Biological Activity
The results revealed that Compounds 5a, 5b, and 5e showed high activity, compounds 3a, 3b, 3c, and 5f
have shown moderate activity, rest of the compounds are low antibacterial activity against the
Staphylococcus aureus. Compounds 3b, 5a, and 5b showed high activity, compounds 3a, 3c, 5c, and 5e
have shown moderate activity, remaining compounds exhibited low activity against lactobacillus
acidophilus. Compounds 3b, 5a, 5b, 5e, 5f, and 3c, 5c have shown high activity and moderate activity
respectively, the remaining compounds showed low activity against Escherichia coli. Apart from the
individual study, 5a, and 5b bearing 4-SO2-CH3, and 2,4-difluoro groups on the phenyl sulfonamide ring
showed good activity. Compound 3b bearing 2-pyridyl amide ring showed good activity in
Staphylococcus aureus and Escherichia coli. In addition, compounds 5e and 5f exhibited good activity,
against Escherichia coli-negative bacteria in presence of cyclopropyl and 2,3-dimethyl isoxazole
sulfonamide functionality. The majority of the compounds having electron-withdrawing groups showed
antibacterial activity against the bacteria. The obtained antibacterial activity result is presented in Table-1.
Vol. 16 | No. 1 |527-535| January - March | 2023
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ROSUVASTATIN SUBSTITUTED PIPERAZINYL-ARYL AMIDE Donka Suresh Babu et al.
Table-1: Antibacterial Activity of Compounds 3(a-d), 4(a-d) and 5(a-h)
Diameter of the
inhib
ition
zone
(in mm) at conc. 200
µ
g/mL
Compound Staphylococcus
aureus
Lactobacillus
acidophilus
Escherichia
coli
Standard drug
(Streptomycin)
3a 0. 6 0. 5 0. 3 1. 5
3b
0. 8
0. 9
1. 2
1. 5
3c 0. 6 0. 5 0. 8 1. 5
3d
0. 3
--
--
1. 5
4a 0. 2 -- -- 1. 5
4b 0. 3 -- -- 1. 5
4c
0. 2
--
0.
3
1
.
5
4d -- -- -- 1. 5
5a 1. 2 1. 0 1. 6 1. 5
5b
1. 0
0. 8
1. 4
1. 5
5c 0. 4 0. 6 0. 8 1. 5
5d -- -- -- 1. 5
5e 0. 9 0. 6 1. 2 1. 5
5f 0. 6 0. 4 1. 0 1. 5
5g 0. 2 -- 0. 4 1. 5
5h -- 0. 4 -- 1. 5
The antifungal results revealed that compounds 3a, 5b, 5c, 5e, and 5f have shown good antifungal activity
against the tested bacterial strains. And, compound 3b bearing the 2-pyridyl amide group has shown
effective antifungal activity against tested microbes, while the rest of the compounds have shown
moderate antifungal activity against the Clostridium tetani strain. The results of the antifungal activity
testing are shown in Table-2.
Table-2: Antifungal Activity of Compounds 3(a-d), 4(a-d) and 5(a-h)
Zone of
I
nhibi
tion (in mm) at conc. 200
µ
g/mL
Compound Clostridium
tetani
Aspergillus
Niger
Aspergillus
fumigates
Trichoderma
3a
1.0
1.2
0.9
0.6
3b
1.2
1.6
1.8
1.4
3c
1.2
0.2
--
--
3d
1.2
--
0.4
0.6
4a
1.2
--
--
--
4b
1.2
--
--
--
4c
1.2
--
--
--
4d
1.2
--
0.
8
1.3
5a
--
--
--
--
5b
1.0
0.
6
0.
6
1.1
5c
1.3
1.0
0.8
0.4
5d
--
--
--
1.3
5e
1.4
0.9
0.8
1.2
5f
1.2
0.4
0.7
1.0
5g
--
--
--
1.0
5h
--
--
0.9
--
Nystatin
2.5
2.5
2.5
2.5
CONCLUSION
Title compounds 3(a-d), 4(a-d), and 5(a-h) were synthesized and characterized by different spectroscopic
techniques. Titled compounds 3a, 3b, 5a, 5b, 5e, 5f and 5c have shown good to moderate antimicrobial
activity. The above results revealed that the significance of amide and sulfonamide analogues may be
Vol. 16 | No. 1 |527-535| January - March | 2023
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ROSUVASTATIN SUBSTITUTED PIPERAZINYL-ARYL AMIDE Donka Suresh Babu et al.
efficient drug candidates designed for the action of diverse bacteriological contagions instigated through
multi-drug unaffected pathogens.
ACKNOWLEDGMENTS
The authors express their gratitude to the DST-PURSE Center, Sri Venkateswara University, Tirupati,
Andhra Pradesh considered for supporting analytical and screening antimicrobial activities. Further, we
express sincere thanks to Associate Prof. B. Gangaiah, Department of Business Management, Associate
Prof. M. Subhosh Chandra, Department of Microbiology and Mr. K. Yelamanda Rao, Department of
Chemistry, Y. V. University, Kadapa for giving the plagiarism report.
CONFLICT OF INTERESTS
All the authors declare that there is no conflict of interest.
AUTHOR CONTRIBUTIONS
All the authors contributed significantly to this work, took part in its reviewing, editing, and
characterizing, and gave their final approval for publication. The author’s ORCID IDs which is listed
below can be used to confirm their research profile.
Suresh Babu Donka http://orchid.org/0000-0002-0038-0731
Srinivasulu Doddaga http://orchid.org/0000-0002-1194-2445
Bala Yesu Valaparla http://orchid.org/0000-0003-3405-0260
Murali Vatturu http://orchid.org/0000-0003-4986-8305
VVPC Narayana http://orchid.org/0000-0002-9565-9785
Sajitha Kethineni http://orchid.org/0000-0003-2628-7989
Meriga Balaji http://orchid.org/0000-0001-9238-5523
Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give appropriate credit to the original
author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were
made.
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[RJC-8008/2022]
