Synthesis, Characterization, and Pharmacokinetic Studies of Thiazolidine-2,4-Dione Derivatives

Ansari, Bushra; Khan, Haroon; Jan, Muhammad Saeed; Alsharif, Khalaf F.; Alzahrani, Khalid J.; Rashid, Umer; Pirzada, Abdul Saboor

doi:https://doi.org/10.1155/2023/9462176

Journal of Chemistry

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Abstract Introduction Materials and Methods Results Discussion Conclusion Data Availability Conflicts of Interest Supplementary Materials References Copyright Related Articles

Research Article | Open Access

Volume 2023 | Article ID 9462176 | https://doi.org/10.1155/2023/9462176

Synthesis, Characterization, and Pharmacokinetic Studies of Thiazolidine-2,4-Dione Derivatives

Bushra Ansari,¹Haroon Khan,¹Muhammad Saeed Jan,²Khalaf F. Alsharif,³Khalid J. Alzahrani,³Umer Rashid,⁴and Abdul Saboor Pirzada¹

Academic Editor: Vinod Kumar Tiwari

Received20 Sept 2022

Revised16 Dec 2022

Accepted04 Jan 2023

Published16 Jan 2023

Abstract

Various derivatives of thiazolidine-2,4-dione (C1–C5) were designed and synthesized by chemical reaction with 4-nitrobenzaldehyde using Knoevenagel reaction conditions which results in the reduction of nitro group to amine and further modification results in target compounds. The chemical structures of all the 2,4-thiazolidinedione derivatives have been elucidated by ¹H and ¹³C NMR spectroscopy. These compounds were further characterized by in silico ADME (absorption, distribution, metabolism, and excretion) studies. The pharmacokinetic properties were assessed by SwissADME software. The in silico ADME (absorption, distribution, metabolism, and excretion) assessment reveals that all derivatives (C1 to C5) have 5 to 7 rotatable bonds. Lipophilicity and water solubility showed that C1, C2, and C4 are water soluble except for C3 and C5 which are moderately soluble. All the compounds have high GI absorption except C3. None of the derivatives are blood-brain barrier permeant. Drug metabolism of TZDs derivatives showed that C3 was identified as an inhibitor of CYP2C9 and C5 as an inhibitor of CYP1A2 and CYP2C19. Drug likeness properties indicate that C1 has only one violation of the Ghose rule while C3 has violations in the Ghose and Egan rules. The in silico pharmacokinetic studies revealed high GI absorption and the inability to pass blood-brain barrier which can be further assessed by in vitro and in vivo antihyperglycemic activity. This study will contribute to providing TZDs derivatives with an improved pharmacokinetic profile and decreased toxicity.

1. Introduction

Thiazolidine-2,4-dione (TZDs) or glitazones are a class of heterocyclic compounds containing a five-membered thiazolidine group and carbonyl groups at positions 2 and 4. Only the 3 and 5 positions enable various substitutions; however, the substitution at position 2 results in the most significant modification to the structure and characteristics of TZDs. These heterocyclic moieties having nitrogen and sulfur known as thiazoles such as 1,3-thiazolidine-2,4-diones, The application of 4-(4-benzoylaminophenoxy)phenol analogues in a wide variety of pharmacological activities has sparked significant interest in several fields of medicinal chemistry [1, 2]. TZDs are now approved for use in the treatment of type 2 diabetes patients with poor glycemic control despite receiving the maximum tolerable dose of oral monotherapy with either metformin or sulphonylurea. TZDs should only be administered with metformin in individuals who are obese, according to general recommendations [3]. TZDs such as ciglitazone, pioglitazone, troglitazone, rosiglitazone, and a new agent, lobeglitazone [4], are widely used as effective antidiabetic drugs, etc. Through the stimulation of the peroxisome proliferator-activated receptor gamma (PPARγ), these drugs make fat cells more sensitive to insulin [1]. It has been proposed that PPARγ activates endothelial nitric oxide synthase, which is crucial for cardioprotection [5, 6]. Human kidneys and target tissues for insulin action, such as adipose, skeletal muscles, and liver tissues, are the organs where PPAR receptors are produced. The transcription of insulin-responsive genes involved in the regulation, synthesis, transport, and use of glucose is controlled by the activation of PPAR nuclear receptors [7]. It has been demonstrated that TZDs increase the insulin sensitivity of adipose, muscle, and liver tissue. TZDs reduce both fasting and postprandial hyperglycemia by reducing insulin resistance and enhancing the efficiency of endogenous insulin. TZDs outperform other antihyperglycemic medications in terms of their ability to reduce hyperglycemia over time [8]. Since TZDs are the only medications that primarily target insulin resistance and recent literature has linked them to side effects like weight gain, edoema, heart failure, anaemia, hepatotoxicity, and bone fractures in women [9], the use of these relatively inexpensive medications justifies a re-evaluation of their clinical use[10]. This grabbed the curiosity of scientists who had developed a variety of TZD derivatives and evaluated them for a range of biological activities. TZDs showed no of pharmacological activities such as hypoglycemic and antihyperlipidemic [11], cardioprotective effect [12], antioxidant activity, MAO inhibitor [13], antimicrobial activity [14], anti-inflammatory activity [15], antituberculosis activity [16], anticancer [17]. In silico ADME studies are anticipated to minimise the risk of late-stage attrition in drug development and increase the testing and screening of the most promising compounds [18]. The present research is designed to synthesize new derivatives of TZDs with improved pharmacokinetic properties and fewer adverse effects.

2. Materials and Methods

2.1. Chemical

The chemicals used were dimethyl sulfoxide (DMSO), methanol, chloroform, ethanol, acetone, sodium bicarbonate, phosphate buffer saline, toluene and piperidine, chloride dehydrate, bromoacetyl bromide, K₂CO_{3, and} tetrahydrofuran.

2.2. General Method for the Synthesis of (C1–C5) Thiazolidine-2,4-Dione Derivatives

Thiazolidine-2,4-dione derivatives were obtained via a double-step protocol, as shown in synthetic Schemes 1 and 2 4-nitrobenzaldehyde undergoes Knoevenagel condensation by thiazolidine-2,4-dione in absolute ethanol with piperidine as the base/condensing agent to yield compound 3. Nitro derivative was reduced to amine (4) by using tin (II) chloride dehydrate. In the second step, amino derivative 4 reacted with bromoacetyl bromide in tetrahydrofuran at 0°C using K₂CO₃ as the base to form mono-bromo derivatives. The synthesized derivative was further reacted with primary or secondary amines to form target derivatives.

2.3. (Z)-N-(4-((2, -Dioxothiazolidin-5-ylidene)Methyl)Phenyl)-2-(Piperazin-1-yl)Acetamide (C1)

Yellow color solid, Yield = 59%, m.p. 197–199°C; R_f = 0.51; (DCM/MeOH; 2 : 1); ¹HNMR (400 MHz, DMSO-d₆) (ppm); 12.11 (brs, 1H, TZD-NH), 8.54 (brs, 1H, NH-CO), 7.74 (d, 2H, J = 8.4 Hz, Ar-H), 7.60 (d, 2H, J = 8.4 Hz, Ar-H), 7.52 (s, 1H, =CH), 3.19 (s, 2H, CH₂), 2.85–2.81 (m, 4H, pip-CH₂), 2.61–2.56 (m, 4H, pip-CH₂), 2.02–1.98 (m, 1H, pip-NH); ¹³CNMR (100 MHz, DMSO-d₆); δ 173.2, 165.7, 162.9, 141.7, 130.3, 127.8, 127.0 (2 carbon), 125.7, 120.4 (2 carbon). 57.6, 53.9 (2 carbon), 47.3 (2 carbon); LCMS: m/z = 347.4 [M + H]⁺. Analysis calculated for C₁₆H₁₈N₄O₃S. C, 55.48; H, 5.24; N, 16.17. Observed value: C, 55.56; H, 5.22; N, 16.15. The 1H, 13C NMR and CHN of the compound C1 is presented in supplementary material as Figures S1–S3.

2.4. (Z)-N-(4-((2,4-Dioxothiazolidin-5-ylidene)Methyl)Phenyl)-2-(4-Methylpiperazin-1-yl)Acetamide (C2)

Pale yellow color solid, Yield = 64%, m.p. 183–185°C; R_f = 0.54; (DCM/MeOH; 2 : 1); ¹HNMR (400 MHz, DMSO-d₆) (ppm); 12.13 (brs, 1H, TZD-NH), 8.54 (brs, 1H, NH-CO), 7.78 (d, 2H, J = 8.4 Hz, Ar-H), 7.62 (d, 2H, J = 8.4 Hz, Ar-H), 7.51 (s, 1H, =CH), 3.18 (s, 2H, CH₂), 2.74 (s, 3H, N-CH₃), 2.23–2.19 (m, 4H, pip-CH₂), 2.02–1.97 (m, 4H, pip-CH2), ¹³CNMR (100 MHz, DMSO-d₆); δ 173.1, 165.6, 162.8, 141.6, 130.2, 127.7, 127.0 (2 carbon), 125.7, 120.4 (2 carbon), 63.0, 52.4 (2 carbon), 51.5 (2 carbon), 44.2; LCMS: m/z = 361.2 [M + H]⁺. Analysis calculated for C₁₇H₂₀N₄O₃S C, 56.65; H, 5.59; N, 15.54; observed value: C, 56.76; H, 5.57; N, 15.55. The 1H, 13C NMR and CHN of the compound C2 is presented in the supplementary material as Figures S4–S6.

2.5. (Z)-N-(4-((2,4-Dioxothiazolidin-5-ylidene)Methyl)Phenyl)-2-(4-(Phenylsulfonyl)Piperazin-1-yl)Acetamide (C3)

Dark yellow color solid, Yield = 54%, m.p. 221–223°C; R_f = 0.50; (DCM/MeOH; 4 : 1); ¹HNMR (400 MHz, DMSO-d₆) (ppm); 12.11 (brs, 1H, TZD-NH), 8.52 (brs, 1H, NH-CO), 7.89 (d, 2H, J = 8.4 Hz, Ar-H), 7.74 (d, 2H, J = 8.0 Hz, Ar-H), 7.64 (m, 5H, Ar-H), 7.52 (s, 1H, =CH), 3.18 (s, 2H, CH₂), 3.29 (t, 4H, J = 5.64 Hz, pip-CH₂), 2.58 (t, 4H, J = 5.64 Hz, pip-CH₂), ¹³CNMR (100 MHz, DMSO-d₆); δ 172.9, 166.0, 162.7, 141.6, 136.2, 130.8, 129.0 (2 carbon), 128.1, 127.0 (2 carbon), 126.6, 126.0 (2 carbon), 121.3 (2 carbon), 60.8, 52.6 (2 carbon), 47.3 (2 carbon); LCMS: m/z = 487.7 [M + H]⁺. Analysis calculated for C₂₂H₂₂N₄O₅S₂, C, 54.31; H, 4.56; N, 11.51; O, 16.44; S, 13.18; observed value: C, 54.39; H, 4.58; N, 11.52.

2.6. (Z)-N-(4-((2,4-Dioxothiazolidin-5-ylidene)Methyl)Phenyl)-2-Morpholinoacetamide (C4)

Yellow color solid, Yield = 73%, m.p. 203–205°C; R_f = 0.48; (DCM/MeOH; 2 : 1); ¹HNMR (400 MHz, DMSO-d₆) (ppm); 12.11 (brs, 1H, TZD-NH), 8.55 (brs, 1H, NH-CO), 7.74 (d, 2H, J = 8.4 Hz, Ar-H), 7.60 (d, 2H, J = 8.4 Hz, Ar-H),7.53 (s, 1H, =CH), 3.73 (t, 2H, J = 6.72 Hz, CH₂), 3.19 (s, 2H, CH₂), 2.67 (t, 2H, J = 6.72 Hz, CH₂); ¹³CNMR (100 MHz, DMSO-d₆); δ 172.6, 165.8, 163.1, 141.8, 130.5, 128.0, 127.4 (2 carbon), 125.9, 120.3 (2 carbon), 65.4 (2 carbon), 62.9, 53.8 (2 carbon). LCMS: m/z = 348.8 [M + H]⁺. The 1H, 13C NMR, and CHN of the compound C4 is presented in supplementary material as Figures S7–S9.

2.7. (Z)-N-(4-((2,4-Dioxothiazolidin-5-ylidene)Methyl)Phenyl)-2-(Piperidin-1-yl)Acetamide (C5)

Light yellow color solid, Yield = 71%, m.p. 181–183°C; R_f = 0.56; (DCM/MeOH; 2 : 1); ¹HNMR (400 MHz, DMSO-d₆) (ppm); 12.13 (brs, 1H, TZD-NH), 8.57 (brs, 1H, NH-CO), 7.76 (d, 2H, J = 8.4 Hz, Ar-H), 7.60 (d, 2H, J = 8.4 Hz, Ar-H),7.53 (s, 1H, =CH), 3.17 (s, 2H, CH₂), 2.61 (t, 4H, J = 5.8 Hz, CH₂), 1.74 (t, 4H, J = 5.4 Hz, CH₂), 1.33 (p, 2H, J = 5.4 Hz, CH₂); ¹³CNMR (100 MHz, DMSO-d₆); δ 172.4, 165.8, 164.2, 141.8, 130.2, 128.0, 127.4, 125.9, 120.3, 64.0, 61.3, 51.6.

2.8. Characterization

The physical appearance of the compounds, R_f values and isolated yields of the pure synthesized compounds were noted separately. Nuclear magnetic resonance (¹H NMR, ¹³C NMR) was used for structure elucidation of the synthesized compounds.

2.9. Pharmacokinetic Studies

In the development and choice of drug candidates, the idea of drug-like chemical spaces is frequently employed. Compounds with pharmacokinetic characteristics that enable them to endure the end of human phase I clinical trials are referred to as drug-like chemical space [19]. The SwissADMET database was used to estimate the physicochemical qualities, such as lipophilicity and water solubility, pharmacokinetic profile, drug likeness, and medicinal chemistry of the compounds [20, 21]. The 2D structures were drawn in the database which also allowed for a string-based search (Table 1).

3. Results

3.1. Chemistry

In Scheme 1, nitro derivative 3 was synthesized by reacting 4-nitrobenzaldehyde (2) with thiazolidinedione (1) in the presence of acetic acid and piperidine in ethanol under reflux condition. The synthesized nitro intermediate was then reduced to amine 4 by using tin (II) chloride dihydrate under reflux conditions in ethanol.

Compound 4 was further reacted with bromo-acetyl bromide in dimethylformamide in the presence of potassium carbonate to obtain monobromo derivative compound 6 which was finally reacted with secondary amines to yield final compounds (C1–C5).

3.2. Analysis of Physicochemical Properties

Out of the five TZDs derivatives, none of them violate Lipinski’s rule of five except C3 which has TPSA of 149.57 Å². This implies their suitability for oral drugs-like molecular nature (Table 2). Molecular weight (MW), No of H-bond donors (nHBD), topological polar surface area (TPSA), Log, and number of hydrogen bond acceptors (NHBAs) of all TZDs derivatives are within the recognized limits of ≤500, ≤5, ≤140 A² and ≤10, respectively (Table 2). The F. Csp³ values for TZDs derivatives range from 0.23 to 0.35 (Table 2). From C1 to C5 all derivatives have 5 to 7 rotatable bonds. The molar refractivity ranges from 98.45 to 136.79 (Figure 1).

3.3. Lipophilicity and Water Solubility

Log _o/w values of all derivatives ranged from 0.68 to 1.82 which reflects its partition preferably into water compartment. Except for C3 and C5 which are predicted as moderately soluble, all other derivatives are water soluble. Log S is aqueous solubility with a defined range of −4∼0.5 log mol/L as shown (Table 3).

3.4. Pharmacokinetics Profile

Pharmacokinetics (PK) of a drug molecule is important to achieve the desired pharmacological goal. This implies that every pharmacokinetic parameter of a compound can eventually affect the pharmacological profile of a drug. The SwissADME database revealed high GI absorption for all derivatives except C3. The boiled-egg graph of C1–C5 is shown in Figures 2–6, respectively. All TZDs derivatives (C1, C2, C4, C5) showed good GI absorption except C3 which is not fit for intestinal absorption. All derivatives from C1–C5 were not able to cross the blood brain barrier. All derivatives are -glycoprotein substrates.

In the case of drug metabolism C3 was identified as an inhibitor of CYP2C9 and C5 as an inhibitor of CYP1A2 and CYP2C19. All other derivatives have no effect on CYP3A4, CYP1A2, CYP2C19, CYP2C9, and CYP2D6. All derivatives have a similar Table 4 bioavailability Table 5 score of 0.55.

3.5. Drug Likeness

C2, C4, and C5 do not violate any of the five drug likeness parameters, i.e., Lipinski, Muegge, Ghose, Veber, and Egan rules of drug likeness. However, C1 has only one violation of the Ghose rule (WLOGP < −0.4). C3 has violations in Ghose (MW > 480, MR > 130), Veber (TPSA > 140), and Egan rules (TPSA > 131.6).

3.6. Medicinal Chemistry

TZDs (C1–C5) derivatives have no PAINSalert; free from α-screen artifacts, frequent hitters, and reactive compounds. Brenk structural alert has identified two reactive groups in TZDs derivatives, i.e., a thioester group and Michael acceptor. C1, C4, and C5 has molecular weight <350, so they have lead likeness capability. C2 and C3 cannot serve as leads as their MW is >350. The SwissADME database has assigned TZDs derivatives scores of 3.16 to 3.84 which represent easy step reactions of synthesis.

4. Discussion

Chemically, thiazolidinediones are heterocyclic rings containing two carbonyl groups at the second and fourth positions that may be modified structurally to create a variety of derivatives [22]. Ciglitazone was the first member of the thiazolidinedione group to be synthesised, and it was followed by the production of additional derivatives including Englitazone, Pioglitazone, and Troglitazone. All of them have a similar thiazolidine-2,4-dione structure, a characteristic that provides them most of their pharmacological effects [23]. Troglitazone, which has the ability to reduce blood sugar levels, was discovered by the Sankyo Company in 1988. In the year 1997, the FDA gave approval for this product for treatment in T2DM. Troglitazone was withdrawn from the UK market six weeks after Glaxo Wellcome launched it due to a rare but potentially deadly idiosyncratic hepatotoxicity, and the FDA removed completely it in March 2000. The first TZD, Ciglitazone, was found in 1982 after intensive research on the structure-activity connection. Animal models showed Ciglitazone to have potential lipid- and glucose-lowering effects. However, this chemical was eventually stopped due to severe liver damage [24, 25]. In the present study, thiazolidine-2,4-dione intermediates were synthesized by using Knoevenagel reaction conditions. Knoevenagel condensation is considered as a variant of the Aldol condensation, and it is a classical method for the synthesis of C-C bond formation. A key step in the synthesis of the medicinally important antidiabetic Glitazone family involves Knoevenagel condensation. 5-arylidene-2,4-thiazolidinediones core is synthesized by the condensation reaction of thiazolidine-2,4-dione with aldehydes. Only Z-configuration was obtained by adding an arylidene moiety to thiazolidine-2,4-dione, according to published data from X-ray diffraction and NMR investigations. TZDs are a significant class of medications that work by enhancing the transactivation activity of PPARs. As a result, they decrease hepatic glucose production while increasing peripheral glucose utilization and lipid metabolism. The preload and afterload on b-cells and lipid homeostasis are thus decreased as a result of these effects.he impact of endogenous insulin improves in order to maintain blood glucose levels. Rationalized techniques have been employed to continue expanding antidiabetic TZDs group in light of current developments and a better knowledge of the structure and operations of other antidiabetic targets. More recent approaches are based on the structural considerations of the ligands and receptors and the interactions between ligands and receptors [26, 27].

The pharmacokinetic analysis of TZDs C1–C5 showed that Lipinski’s rule of five is necessary for rational drug development. Any drug molecule violating even one of the rules may have low permeability or poor absorption [28]. Fsp³ is the fraction of sp³ carbon atoms out of the total carbon count. This reflects the carbon saturation and characterizes complexity of the molecular spatial structure. A suitable value considered optimum for Fsp³ is ≥0.42, as about 84% of commercial drugs meet this criterion [29]. However, sp³ content needs to be increased within a range because a higher Fsp³ score is not a guarantee of higher performance and can increase the difficulty of chemical synthesis [30]. Synthetic products usually have a lower fraction of sp³ than natural molecules, and so natural products are a rich source of drugs [31]. Rotatable bond count is employed as “drug filter” which is correlated with reduced rat oral bioavailability if the number of rotatable bonds is greater than 10 [32]. Mechanistically utilizing “rotatable bond filter” is still unclear, as its count does not correlate with the in vivo clearance rate in rats. However, the filter is justified from an in vitro screening prospect because ligand affinity decreases at an average of 0.5 kcal for each two rotatable bonds [33]. The H-bond acceptor and donor are within accurately strict limit, except C3 being within limit but a little higher nRB and nHBA (Table 2). Oral drugs have fewer H-bond acceptors, donors, and rotatable bonds [20]. These three parameters favor oral route of administration as being flexible, convenient, and simple one.

The molecules with a TPSA of ≥140 Å² would be poorly absorbed with less than 10% fractional absorption, while those with a TPSA of 60 Å² would be well absorbed with greater than 90% fractional absorption [34]. C1, C2, C4, and C5 are predicted to have better absorption as reflected from TPSA, however, C3 has a TPSA of 149.57 Å² suggestive of poor oral absorption.

The Log _o/w calculated by SwissADME is an average of iLOGP, XLOGP3, WLOGP, MLOGP, and SILICOS-IT, referred to as the consensus Log _o/w. Log _o/w is the Log of the octanol/water partition coefficient. A higher log _o/w value indicates higher lipophilicity, and it depends upon polarity, molecular size, and hydrogen bonding. Log _o/w values of all derivatives ranged from 0.68 to 1.82 which reflects their partition preferably into the water compartment. However, the values of log _o/w exhibit optimal lipophilicity (Optimal: 0 < Log ) [35]. These values are somewhat congruent with log S values. The SwissADME database revealed high GI absorption for all derivatives except C3 [21].

None of TZDs derivatives are predicted to cross blood-brain barrier. This will minimize or eradicate the chances of CNS toxicity. All TZDs derivatives are substrates of p-glycoprotein. This may associate them in interactions with different endogenous or exogenous chemicals, especially drugs. -glycoprotein interactions may ultimately affect the pharmacological profile of other drugs [36]. CYP3A4 is one of the most important isoforms of the CYP P450 system metabolizing majority of drugs and endogenous chemicals. All derivatives are predicted to have no effect on CYP3A4, indicating a diminished number of interactions. In a similar pattern all the derivatives do not affect other important isoforms like CYP1A2, CYP2C19, CYP2C9, and CYP2D6, except that C3 is an inhibitor of CYP2C9 and C5 is an inhibitor of CYP1A2 and CYP2C19. This may involve C3 and C5 in pharmacokinetic drug interactions. The bioavailability score indicates a good enough plasma concentration. The calculation of bioavailability and permeability is important before proceeding for the synthesis or any advanced testing. Therefore, a probability-based score is given to a drug candidate to have F > 10% in rat [37]. C2, C4, and C5 are compliant with many widely acceptable drug likeness rules, i.e., Lipinski, Muegge, Ghose, Veber, and Egan. However, C1 has a single violation of solubility, while C3 has a high TPSA value, MR, and molecular weight. This is a violation of Ghose, Veber, and Egan rules. However, there was no problem identified in the absorption of four derivatives as defined by the boiled-egg graphical representation. The yellowish region on the boiled-egg graph represents CNS penetration; the white region represents human intestinal absorption. If the drug absorption is other than oral, it will be represented in the gray area of the graph [21].

All TZDs derivatives (C1, C2, C4, and C5) showed good GI absorption except C3 which is not fit for intestinal absorption. None of the derivatives are blood brain barrier permeant, indicating a positive gesture of being free of CNS toxicity. All derivatives are -glycoprotein substrates. TZDs derivatives have “zero” PAINS (Pan Assay interference compounds) alert, and so excluded from the list of α-screen artifacts, frequent hitters, and reactive compounds. PAINS have an unrestrained behavior of producing false positive hits during HTS. The mechanism is poorly understood; however, it is associated with protein reactivity and noncovalent interactions [38]. In SwissADME a structural alert is created for 105 fragments identified by Brenk et al. which are chemically reactive, toxic, metabolically unstable, or likely to have poor pharmacokinetics. This can identify a problematic fragment found in a given molecule [39]. This structural alert has identified two reactive groups, i.e., a thioester group and Michael acceptor. A thioester group is present in these five TZD derivatives, and MedChem rules consider a thioester fragment as potentially reactive or promiscuous [40]. Considering this observation, these compounds can be considered for structural optimization. Thioesters are acylating agents which give rise to hydrolysis products that interfere with assays [41]. In the same manner, Michael acceptor can prove to be reactive and contribute to side effects [42]. However, this can be correlated with the preclinical studies carried out which are available at this stage. Lead likeness parameter represents the ability of a molecule to serve as “lead” in the drug discovery process. C1, C4, and C5 have a molecular weight <350, so they have lead-likeness capability. On the basis of SAR, their pharmacophores can be modified further to achieve better pharmacological results. C2 and C3 have violated one of the lead-likeness rules as their MW is >350. Therefore, these two molecules are unable to become lead molecules. TZDs (C1–C5) derivatives have been synthesized in the lab. However, the SwissADME database prediction of its synthetic accessibility is congruent to the actual situation. The SwissADME database has assigned to TZDs derivatives the scores of 3.16 to 3.84 which suggest easy step reactions of synthesis. The difficult synthetic approaches for those molecules having a score of 10 [20].

5. Conclusion

In the present research, we have successfully synthesized 2,4-thiazolidinedione derivatives (C1–C5) under Knoevenagel reaction conditions. Most of the derivatives of TZD display higher GI absorption and have good water solubility. In the present study it is concluded that most of derivatives of thiazolidinedione (C1, C2, C4, and C5) has improved pharmacokinetic properties. These targeted agents may contribute to newer antihyperglycemic drugs with higher PK properties. Furthermore, in our lab, we were working on these compounds for their in vitro, in vivo studies and docking studies which will confirm their antihyperglycemic activity.

Data Availability

The required data can be provided upon reasonable request to the corresponding author..

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Supplementary Materials

Figure S1: ¹H NMR of compound C1; Figure S2: ¹³C NMR of compound C1; Figure S3: CHN of compound C1; Figure S4: ¹HNMR of compound C2; Figure S5: ¹³C NMR of compound C2; Figure S6: CHN of compound C2; Figure S7: ¹HNMR of compound C4; Figure S8: ¹³C NMR of compound C4; and Figure S9: CHN of compound C4. (Supplementary Materials)

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