1,3,4-Thiadiazole: A Promising Pharmacophore

Introduction

Fitness and ailment are the aspects of the lifestyles. Wholesome peoples can serve higher for the society and the clinical community is successfully maintaining their fitness issues. It is medicinal chemistry that powers this scientific strategy. Chemotherapeutic potential of different heteroatom moieties, viz. triazoles, azetidinones, thiazolidinones, thiadiazoles, coumarins, quinolines, indoles and many others; enlightened by medicinal chemistry. It is estimated that more than 85% of all FDA-approved drugs in the market are simply heterocyclic molecules. It is believed that within the approaching decade, an extra phase of novel heteroatoms-based current drug designed synthesis is to come back. There has been a rapid growth marked in studies of heterocyclic moieties as a result of emerging synthetic methodologies such as highly electron-donating, strong coordination abilities, metal-catalyzed cross-coupling and hetero-coupling reactions, that facilitates medicinal research workers for the speedy development of a vast range of bioactive heterocyclic derivatives.

Nonetheless, antimicrobial resistance (AMR) has been identified by the WHO as the greatest health hazard to the world today. The improper and excessive use of antimicrobial agents is a key contributor to the development of antibiotic resistance. We need a world-wide push from the scientific community to achieve sustainable improvement dreams (SDGs). It is found that several heterocyclics considered as privilege structural units.  Frequent literature survey evidenced the various pharmacology of diverse  nitrogen, sulphur, bearing heteroatomic mimics. Furthermore, substituted heterocyclic moieties bearing thiadiazole [1-9], quinoline [10-17] and piperazine [18-24] demonstrated great biological profiles.

Scheme 1 Click here to View Scheme

We have preferred quinoline and thiadiazole as our two building blocks in the context of literature analysis. Information explored the approaches of thiadiazole ring as many therapeutic agents are in marketplace with  unique names like acetazolamide used as carbonic anhydrase inhibitors, methazol amide as diuretic medicines, cefazolin (1st generation of cephalosporin) sulfonamide, sulfamethizole both as antimicrobial  drugs  while megazol as antiparasitic agent. At the same time, quinoline bearing derivatives are also properly famed as existing drug in market for their versatile scientific uses like quinine, chloroquinine, amodiaquine, mefloquine for malaria, carteolol for high blood pressure, angina, ciprofloxacin, ofloxacin, moxifloxacin, levofloxacin, lomefloxacin, enrofloxacin, norfloxacin for bacterial remedy. By reviewing these encouraging pharmacological properties, we continue our work on the design, synthesis, and organic assessment of several targeted substituted thiadiazole congeners in order to attain our novel heterocyclic moiety development programme [25–30]. Based on our research, we chose two building blocks: quinoline and thiadiazole. Data examined the use of the thiadiazole ring because there are numerous medicinal drugs available on the market under various names, such as acetazolamide, which are utilised as carbonic anhydrase inhibitors, methazol amide as diuretic medicines, cefazolin (1^st generation cephalosporin) sulfonamide, sulfamethizole both as antimicrobial agents while megazol as antiparasitic drug. While on the other side, quinoline bearing derivatives are also well famed as drug market for their versatile clinical uses viz. quinine, chloroquinine, amodiaquine, mefloquine for malaria, carteolol for hypertension, angina, ciprofloxacin, ofloxacin, moxifloxacin, levofloxacin, lomefloxacin, enrofloxacin, norfloxacin for bacterial treatment.

scheme2

Scheme 2 Click here to View Scheme

Scheme 3 Click here to View Scheme

Scheme 4 Click here to View Scheme

By developing, synthesizing, and biologically evaluating a number of targeted substituted thiadiazole congeners, we move on with our development programme of novel heterocyclic moieties [25–30] in light of the aforementioned research of these promising pharmacological characteristics.

Results and Discussion

1-(p-tolyl)-1H-[1,3]oxazino[5,6-f]quinolin-3-one 1 was prepared by refluxing of acetophenone, carbamide with quinolin-5-ol in ethanol. By using phosphorous oxychloride to chlorinate derivative 1 was chlorinated to yield 3-chloro-1-(p-tolyl)-1H-[1,3]oxazino[5,6-f] quinoline 2. Derivative (1-(p-tolyl)-1H-[1,3] oxazino[5,6-f]quinolino)-4-piperazine   i.e., 3 obtained by the condensation reaction between derivative 2 and piperazine. Refluxing of derivative 3 and 5-phenyl-2-amino-1,3,4-thiadiazoles [31] furnished the target mimics [2-phenyl-1-(p-tolyl)pyrido[3,2-f]quinazolin-4(1H)-yl]-1,3,4-thiadiazolyl)]-4-piperazine 4a-4i. A total of six microbial strains were designated for in vitro antimicrobial activity of target congeners 4a-4i. Among the three bacteria, one was Gram-positive Staphylococcus aureus while 2 others were Gram-negative; Proteus vulgaris and Escherichia coli. Antifungal testing was performed on Aspergillus fumigatus (plant isolate), Candida krusei G03 and Candida albicans ATCC 2091. Furthermore, thiadaizole scaffolds were also tested for insecticidal screening in groups of cockroaches (Periplaneta americana).

Materials and Methods

Materials

S D Fine Chem Limited (SDFCL), Qualigen Fine Chemicals and E. Merck Ltd., selected for raw materials for the preparation. Fluconazole and ampicillin trihydate antimicrobials were obtained from Ind-Swift Pharmaceuticals and parathion from Joshi Agrochem Pharma Pvt. Ltd. Derivatives were tested for their physical characterization. TLC performed over the silica gel coated glass plates to know the endpoint of the synthesis. Spots visualization was performed in iodine chamber. Heraeus CHN fast analyzer was used to conduct elemental analysis of all derivatives, and Results were found to be within 0.4 percent of their theoretical counterparts. For infrared spectroscopy, the KBr pellets used with FTIR spectrometer (Perkin Elmer system 2000) while Bruker DPX 200 for ¹H-NMR spectroscopy.

Antimicrobial activity

Filter paper disc diffusion methodology [32-33] adopted for performed in vitro antimicrobial activity. Inhibition zone’s diameter was calculated in mm. Nutrient agar has been utilized as culture medium. Culture medium was developed by using sabourad dextrose agar. A concentration of 250g/ml in 10% DMSO and prepared compounds. Ampicillin trihydrate and fluconazole employed as standards for both the activity.

Insecticidal activity

Microlitre syringe method [34]was adopted for the insecticidal activity. Groups maintained and each group contained six cockroaches. 4^th along with 5^th abdominal segments of ventral side of insect was selected to insert acetonic solution of standard parathion (0.02mL of 5g/L) and different test compounds by microliter syringe. Acetone used as control. During insecticidal activity, no food was given and the time taken until 100% mortality was recorded. Student’s t-test was used to assess both the standard and calculated data for statistical significance.

Experimental

Synthesis of 1-(p-tolyl)-1H-[1,3]oxazino[5,6-f]quinolin-3-one (1)

Quinolin-5-ol, carbamide and acetophenone have been mixed in ethanol during stirring for 10 minutes at room temperature before refluxing for 1.5 hours. On completion, the reaction mixture has been cooled by being put into ice-water while being stirred, filtered, and then recrystallized using methanol: R_f: 0.69, m.p: 171 ⁰C; Yield: 67%. “IR (cm⁻¹): 1279 (-C-O-C-), 1588 (-C=N-), 1620 (-C…C- aromatic ring), 1742 (C=O), 3420 (NH). ¹H-NMR (CDCl₃, δ): 2.33 (s, 3H, -CH₃), 4.70 (s, 1H, CH-NH), 6.75 (bs, 1H, -NH-), 7.40-8.66 (m, 9H, H-Ar). Anal. calcd. for C₁₈H₁₄N₂O₂: N, 9.65; H, 4.86; C, 74.47; found N, 9.57; H, 4.88; C, 74.66. MS (m/z, %) 290.11.”

Synthesis of 3-chloro-1-(p-tolyl)-1H-[1,3]oxazino[5,6-f] quinoline (2)

Compound 1 was dissolved in toluene and heated to a reflux for 1.5 hours before phosphorous oxychloride (0.015mol) was added drop by drop. Extra toluene was removed using distillation. After being put into cold water and stirred, the reaction mixture was neutralised with 3 percent KOH solution, recrystallized, and filtered in ethanol: “R_f: 0.72, m.p: 133 ⁰C, Yield: 62%, IR (cm⁻¹): 1620 (-C…C- aromatic ring), 1285 (-C-O-C-), 1580 (-C=N-). ¹H-NMR (CDCl₃, δ): 2.89 (s, 3H, -CH₃), 4.88 (s, 1H, CH-N-C), 7-38-8.56 (m, 9H, Ar-H). Anal. calcd. for C₁₈H₁₃ClN₂O: N, 9.07; H, 4.24; C, 70.02;  found N, 9.12; H, 4.17, C, 70.14. MS (m/z, %) 308.07”.

Synthesis of (1-(p-tolyl)-1H-[1,3] oxazino[5,6-f]quinolino)-4-piperazine  (3)

Compound 2 and piperazine anhydrate mixed in a methanolic solution for 15 minutes at 40 °C before refluxing for 2.5 hours. The methanol solvent was distilled until there was no excess, and then chilled ice water poured to the residue, washed, and filtered. Crude was recrystallized in aqueous ethanol: R_f: 0.67; m.p.: 156 ⁰C; Yield: 70%. IR (KBr, cm⁻¹): 1616 (C…C of aromatic ring), 1273 (C-O-C), 1571 (C=N). ¹H-NMR (CDCl₃, δ/ppm): 1.70-2.66 (m, 9H, piperazine), 2.80 (s, 3H, -CH₃),  4.78 (s, 1H, CH-N-C), 7.27-8.44 (m, 9H, Ar-H), Anal. calcd. for C₂₂H₂₂N₄O: N, 15.63; H, 6.19; C, 73.72; found N, 15.47; H, 6.11; C, 73.68. MS (m/z, %) 358.18.

Synthesis of [2-phenyl-1-(p-tolyl)pyrido[3,2-f]quinazolin-4(1H)-yl]-1,3,4-thiadiazolyl)]-4-piperazine (4a-4i)

Derivative 3 (0.002 mol) and 2-amino-5-phenyl-1,3,4-thiadiazole (0.002 mol) were refluxed in isopropanol for 2-3 hours. Distillation has been used to retrieve solvent once the process of preparation was finished. The necessary compounds 4a-4i were obtained by dumping the residue into broken ice, washing it with petroleum ether (40-60°C), and then recrystallizing it in the suitable solvents.

Compound 4a

R_f: 0.66; m.p.:231⁰C; Yield: 58%. “IR (cm⁻¹): 1625 (-C…C- aromatic ring), 681 (C-S-C), 1289 (-C-O-C-), 1360 (-N-N-), 1598 (-C=N-). ¹H-NMR (CDCl₃, δ): 1.58-2.60 (m, 9H, piperazine), 2.95 (s, 3H, -CH₃), 4.65 (s, 1H, -CH-N-C-), 7.51-8.75 (m, 14H, H-Ar), Anal. calcd. for C₃₀H₂₇N₇S: N,18.94; H, 5.26; C,69.61; found N,19.18; H,5.20; C,69.55. MS (m/z, %) 517.20.

Compound 4b

R_f: 0.70; m.p.:111⁰C; Yield: 43%. IR (cm⁻¹): 1615 (-C…C- aromatic ring), 673 (-C-S-C-), 1281 (-C-O-C-), 1366 (-N-N-), 1577 (-C=N-). ¹H-NMR (CDCl₃, δ): 1.63-2.50 (m, 9H, piperazine), 3.05 (s, 3H, -CH₃),  4.79 (s, 1H, -CH-N-C-), 7.55-8.70 (m, 13H, H-Ar). Anal. calcd. for C₃₀H₂₆N₇ClS: N,17.76; H,4.75; C,65.26; found N,17.85; H,4.70; C,65.40. MS (m/z, %) 551.17.

Compound 4c

Yield: 51%; R_f: 0.64; m.p.:130⁰C. IR (cm⁻¹): 1620 (-C…C- aromatic ring), 670 (-C-S-C-), 1272 (-C-O-C-), 1351 (-N-N-), 1590 (-C=N-). ¹H-NMR (CDCl₃, δ): 1.60-2.62 (m, 9H, piperazine), 3.00 (s, 3H, -CH₃),  4.56 (s, 1H, -CH-N-), 7.33-8.72 (m, 13H, H-Ar), Anal. calcd. for C₃₀H₂₆N₇ClS: N,17.76; H,4.75; C,65.26; found N,17.65; H,4.61; C,65.18. MS (m/z, %) 551.17.

Compound 4d

R_f: 0.56; m.p.:106⁰C; Yield: 52%. IR (cm⁻¹): 1618 (-C…C- aromatic ring), 692 (-C-S-C-), 1282 (-C-O-C-), 1358 (-N-N-), 1584 (-C=N-). ¹H-NMR (CDCl₃, δ): 1.45-2.56 (m, 9H, piperazine), 3.10 (s, 3H, -CH₃),  4.48 (s, 1H, -CH-N-), 7.40-8.68 (m, 13H, H-Ar). Anal. calcd. for C₃₀H₂₆N₇ClS: N,17.76; H,4.75; C,65.26; found N,17.86; H,4.70; C,65.22. MS (m/z, %) 551.17.

Compound 4e

R_f:0.62; m.p.:154⁰C; Yield:62%. IR (cm⁻¹): 1650 (-C…C- aromatic ring), 688 (-C-S-C-), 1280 (-C-O-C-), 1360 (-N-N-), 1590 (-C=N-). ¹H-NMR (CDCl₃, δ): 1.50-2.50 (m, 9H, piperazine), 2.94 (s, 3H, -CH₃), 4.60 (s, 1H,-CH-N-), 7.47-8.70 (m, 13H, H-Ar). Anal. calcd. for C₃₀H₂₆N₈O₂S: N,19.92; H,4.66; C,64.04; found N,20.07; H,4.59; C,64.23. MS (m/z, %) 548.17.

Compound 4f

R_f:0.65; m.p.:138⁰C; Yield:57%. IR (cm⁻¹): 1641 (-C…C- aromatic ring), 681 (-C-S-C-), 1267 (-C-O-C-), 1343 (-N-N-), 1600 (-C=N-). ¹H-NMR (CDCl₃, δ): 1.48-2.61 (m, 9H, piperazine), 3.05 (s, 3H, -CH₃),  4.55 (s, 1H, -CH-N-), 7.33-8.61 (m, 13H, H-Ar). Anal. calcd. for C₃₀H₂₆N₈O₂S: N,19.92; H,4.66; C,64.04; found N,19.89; H,4.70; C,64.12. MS (m/z, %) 548.17.

Compound 4g

R_f:0.68; m.p.:201⁰C; Yield: 65%. IR (cm⁻¹): 1637 (-C…C- aromatic ring), 681 (-C-S-C-), 1289 (-C-O-C-), 1360 (-N-N-), 1563 (-C=N-). ¹H-NMR (CDCl₃, δ): 1.51-2.59 (m, 9H, piperazine), 3.02 (s, 3H, -CH₃), 3.63 (s, 3H, -OCH₃), 4.66 (s, 1H, -CH-N-), 7.39-8.61 (m, 12H, H-Ar), 12.50 (bs, 1H, HO-Ph). Anal. calcd. for C₃₁H₂₉N₇SO₂: N,17.39; H,5.19; C,65.05; found N,17.55; H,5.31; C,64.93. MS (m/z, %) 563.21.

Compound 4h

R_f:0.70, m.p.: 173⁰C; Yield:58%. IR (cm⁻¹): 1656 (-C…C- aromatic ring), 1565 (-C=N-), 1367 (-N-N-), 1249 (-C-O-C-), 682 (-C-S-C-). ¹H-NMR (CDCl₃, δ): 1.02 (s, 3H, -CH₃), 1.58-2.45 (m, 9H, piperazine), 3.11 (s, 3H, -CH₃), 4.90 (s, 1H, -CH-N-), 7.34-8.55 (m, 13H, H-Ar).  Anal. calcd. for C₃₁H₂₉N₇S: N,18.44; H,5.50; C,70.03; found N,18.50; H,5.41; C,69.87. MS (m/z, %) 531.22.

Compound 4i

R_f:0.64; m.p.:125⁰C; Yield:51%. IR (cm⁻¹): 1625 (-C…C- aromatic ring), 681 (-C-S-C-), 1289 (-C-O-C-), 1360 (-N-N-), 1598 (-C=N-). ¹H-NMR (CDCl₃, δ): 1.58-2.45 (m, 9H, piperazine), 3.11 (s, 3H, -CH₃), 4.51 (s, 1H, -CH-N-), 7.35-8.61 (m, 13H, H-Ar), 12.35 (bs, 1H, HO-Ph).  Anal. calcd. for” C₃₀H₂₇N₇SO: N,18.37;  H,5.10; C,67.52; found N,18.26; H,4.98;  C,67.67. MS (m/z, %) 533.20.

Table I: Antibacterial and antifungal screening of [2-phenyl-1-(p-tolyl)pyrido[3,2-f] quinazolin-4(1H)-yl]-1,3,4-thiadiazolyl)]-4-piperazine (4a-4i). Click here to View Table

Table 2: Insecticidal activity of [2-phenyl-1-(p-tolyl)pyrido[3,2-f] quinazolin-4(1H)-yl]-1,3,4-thiadiazolyl)]-4-piperazine (4a-4i). Click here to View Table

Scheme 5 Click here to View Scheme

Conclusion

Insecticidal and antimicrobial activity of compounds 4a-4i evidenced promising biological utility of pharmacophores; thiadiazole, quinoline and piperazine. Clinical results explored that compounds 4b, 4c, 4d and 4i substituted with 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl and 2-hydroxyphenyl respectively showed better pharmacological evaluation. These derivatives possessed statistically good antibacterial and antifungal activity but less than standards used (Table I). Analysis of insecticidal activity cleared that these compounds also displayed prominent insecticidal activity (Table II) in comparison to the parathion at all concentrations used. Various substitution performed well over the block structure thiadiazoles and displayed appropriate orientation to the potential receptor site. Structure activity relationship (S.A.R.) of the compounds 4a-4i revealed that conversion of derivative 3 into different substituted 1,3,4-thiadiazoles 4a-4i via condensation with 2-amino-5-phenyl-1,3,4-thiadiazole improved biological activities. Furthermore S.A.R. revealed that halogen substituted thiadiazoles caused better antimicrobial inhibition. But among these, 2-chlorophenyl substitution found beneficial towards antimicrobial activity while on the other hand 2-hydroxyphenyl substitution caused significant insecticidal potential. Above study cleared the biological potential of quinoline, thiadiazole and piperazine which impelled to explore more in the same stream.

Acknowledgement

We are thankful to the Principal, Dr. Rajesh C. Paliwal and secretary, Harsh Kumar Daulat, H. V. M. P. G. College for their support during the work.

Conflict of Interest

There are no conflict of interest.

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