Advancement and recent trends in seeking less toxic and more active anti-cancer drugs: Insights into thiourea based molecules

1 Introduction

Cancer is one of the most widespread lethal diseases that have an unequivocally devastating effect on human health and increase mortality worldwide [1–3]. It is not a single disease but a combination of different diseases that show uncontrolled growth and proliferation of cells in abnormal ways [4–6]. It has been reported in people of all ages, both developing and developed countries. It is the second leading cause of death after cardiovascular disease [7, 8]. Several attempts were made to search for the most appropriate methods for cancer therapy, and finally, diverse approaches were developed and tested. Chemotherapy is known as the most fundamental technique for treating cancer, consisting of various synthetic and natural compounds that significantly destroy the cancerous cells [9–15]. Although scientists have made rapid progress in chemotherapeutic agents and drug science, cancer treatment is still considered a most significant public health problem due to several reasons, such as resistance, toxicity, and low selectivity of existing anticancer drugs [16–19]. Therefore, to save the lives of millions of people around the world, it is time to discover and develop new active cancer drugs [20, 21]. Over the past several decades, there have been great strides to produce anticancer drugs and the development of numerous novel anticancer agents of both natural and synthetic origin [22–29]. In these compounds, thiourea derivatives act as an imperative core scaffold in various medicinally important compounds [30–37]. Thiourea is a functional organic compound similar to urea, where a sulfur atom replaces the oxygen atom. The presence of sulfur atoms makes the properties of thiourea significantly attractive. It is a white crystalline solid and is also called thiocarbamide or sulforia. There are two tautomeric forms of thiourea as given in Scheme 1, imino (1) and thiol (2) [38]. Thiourea derivatives are the most beneficial pharmaceutically scaffolding and the significant building block for several natural products that have a broad spectrum of fascinating pharmacological properties such as antibacterial, antiparasitic, antifungal, anticancer, antitubercular, antihypertensive, antiobesity, antihistaminic, antineuropathic, antiviral activities, and anti-inflammatory [39–43]. Their anticancer activity has already been reported, which shows valuable efficacy against cancer. Thiourea-based anticancer chemotherapeutic prevents the spread of cancer by inhibiting carbonic anhydrase, protein tyrosine kinase, somatostatin agonists, topoisomerase, and sirtuins [33]. In this study, we have described recent advances in developing bioactive thiourea derivatives to treat different types of cancer. A detailed understanding of the thiourea pharmacophore is also explained through remarkable structure-activity relationship studies (SARs) that enable medicinal chemists to develop novel ideas for further improving rational designs of more active thiourea derivatives based anticancer agents. We hope that this review article will help researchers to design highly potent thiourea derivatives.

2 Anticancer activities of thiourea derivatives

Thiourea derivatives have a variety of biological activities and several applications in the field of medicinal chemistry. This moiety provides a general framework for the extensive varieties of drugs and bioactive compounds with wide-ranging therapeutic and pharmacological properties. The current emergence of anticancer activity of thiourea derivatives has led medicinal chemists to synthesize and design novel thiourea derivatives [33, 40]. The synthesis of novel series (1,2,4-triazole-linked thiourea conjugates) 1–11 (Fig. 1) was performed and their in vitro anticancer activity was tested against different cancer cell lines such as B16-F10 cell line, DU145, A549), MCF-7 and MDA-MB231. The results of these compounds were compared to the reference drug. Compound 6 has revealed substantial cytotoxicity (IC₅₀ = 7.22±0.47μM) in breast cancer cell line (MCF-7) amongst all of the tested compounds and reference drug fluorouracil (IC₅₀ = 16.7±1.5μM).

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Fig. 1

Triazole-linked thiourea conjugates 1–11 with potent anticancer activities.

Moreover, these compounds showed a low cytotoxicity profile against normal human cells (L-132). Overall, studies show that these derivatives possessed the excellent potential for designing novel and potent anticancer drugs [44].

A novel thiourea derivatives 12–49 (Fig. 2a and 2b) were designed and synthesized. The cytotoxic activities of these compounds were tested against multiple cell lines of cancer and HUVECs. Amongst these compounds, 46 consisting of 3,5-bis (trifluoroMethyl) phenyl moiety at the terminal thiourea and phenylamino at the terminal acyl position which indicates stronger antiproliferative activities compared to regorafenib and sorafenib. Furthermore, compound 46 also has the potency to inhibit the clone formation against endothelial cells and cancer cells. It has also shown outstanding antiangiogenic activities regarding the tube formation assay. The molecular docking analysis on the active site of VEGFR-2 was carried out, which shows the binding of the compound into the active site. The absence of substitute to the compound 12 with a phenyl ring has no antiproliferative effects at the concentration of 10μM, indicating the substituent significance on the aromatic ring. Next, several thiourea derivatives were investigated containing electron-donating groups or electron-withdrawing on the aromatic ring. Overall, the electron-withdrawing group is present on the phenyl ring of compounds 15–21, which exhibited outstanding antiproliferative activities. In addition, the presence of 3,5-bis(trifluoromethyl) phenyl on compound 18 shows excellent antiproliferative activities against HUVECs and cancer cell lines. The lowest cell lines activity was reported in the electron-donating compounds 22–27, suggesting that the presence of the electron-donating group on the terminal aromatic ring reduced the antiproliferative activities. Furthermore, fluoro atoms addition at the R2 position has a less central effect on the antiproliferative activity (12–25 vs 28–41). Previous studies confirmed that compounds 18 and 46 show significant activities, considered a promising candidate for anticancer agents [45].

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Fig. 2a

Thiourea derivatives 12–41 with potent anticancer activities.

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Fig. 2b

Thioureaderivatives 42–49 with potent anticancer activities.

A novel thiourea derivatives 50–61 (Fig. 3) were synthesized by treating isothiocyanatebenzodioxole with amino compounds including heterocyclic amines, hydrazines, sulfa drugs, hydrazides, and aromatic amines. Their anticancer activity has been studied against MCF-7, HepG2, and HCT116 cancer cell lines. Typically, these thiourea derivatives have shown a strong cytotoxic effect, while in a few cases more than the doxorubicin. The benzodioxole core and various biologically active pharmacophores were bound to N1 and N2 respectively in the 1,2-disubstituted thioureas and were proven to be safer for normal human cells. N2 binds with benzene sulfonamide that ends with 2-pyridinyl, 2-thiazolyl, acridine, phenylamino, or antipyrine moieties to obtain the most effective activates. The results of the VFITC annexin apoptosis essay stated that HepG2 cells treated with compounds 55 and 57 increased the percentage of apoptotic cells. Thus, it was confirmed that the two tested compounds 55 and 57 can induces apoptosis in the HepG2 cell line. Compounds 55 and 57 arrest the cells effectively in the Pre-G1 phase and at the G2-M phase cause apoptosis. Two compounds 55 and 57 were compared regarding their Bax and Bcl2 values with controls, showing that both compounds cause apoptosis at HepG2 cells. Docking studies showed that thiourea derivatives 54, 55, and 57 have binding modes similar to erlotinib with excellent binding energy [46].

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Fig. 3

Thiourea derivatives 50–61 bearing a benzodioxole moiety with potent anticancer activities.

A series of acyl thiourea derivatives 62–71 (Fig. 4) were designed and synthesized. Anticancer activities of the synthesized compounds were screened against various cancer cell lines. The efficacy of compounds was most valuable against the human ovarian cancer cell line (SK-OV-3), human renal cancer cell line (Caki-2), and cervical cancer cell line (HeLa). The modification of the substituent at the thiourea linkage leads to variables cytotoxic potential of the resulting derivatives towards specific cell lines. In particular, compounds with the function of multiple pyridyl moieties and fluorine have shown anti-cancer effects that can be used as substrates for the further development of chemotherapeutic agents [47].

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Fig. 4

Acyl thiourea derivatives of 7-trifluoromethyl-2-pyridylquinazolin4(3H)-one 62–71 as anticancer agents with excellent anticancer activities.

Novel 1,3,4-thiadiazine-thiourea derivatives 72–87 (Fig. 5) were synthesized and studied further their in vitro cytotoxic activity against (A549) non-small-cell-lung-cancer (NSCLC) cell line. Three compounds 75, 80, 81 exhibited excellent cytotoxic activity (IC₅₀ = 0.27±0.01, 0.30±0.02, and 0.32±0.012μM) respectively in which sorafenib was used as a reference (IC₅₀ = 3.85±0.27μM). These compounds have shown promising results against targets. The promising result of compound 81 showed that the inhibitory activity of VEGFR2 is mostly similar to sorafenib in MMP9 inhibition (IC₅₀ = 0.08±0.004μM), (IC₅₀ = 0.11±0.01μM), most effective B-RAF inhibition activity (IC₅₀ = 0.178±0.004μM). Furthermore, compound 81 was used against A549 cells in the cell cycle analysis, which displayed the arrest of the cell cycle at the G2-M phase: Annexin V-FITC staining showed-apoptotic activity that reflected antimigration and invasive properties to A549 cells. Moreover, the docking of compound 81 on B-RAF, MMP9, and VEGFR2 has shown that it acts as a co-crystallized ligand by similarly binding to the target enzymes. High selectivity of three compounds was observed in the A549 cancer cells against the normal human fetal lung fibroblast cell line WI-38. The selectivity index was greater compared to sorafenib (75 with IC₅₀ = 136.76±2.38μM, SI = 506.52; 80 with IC₅₀ = 89.20±2.11μM, SI = 297.33; 81 with IC₅₀ = 79.60±3.8μM, SI = 248.75; and sorafenib with IC₅₀ = 30.32±2.41μM, SI = 7.88). The overall results of 75, 80, 81, especially 81 indicated that these compounds act as excellent anticancer agents that primarily target the significant NSCLC pathways [48].

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Fig. 5

Novel 1,3,4-thiadiazine-thiourea derivatives with excellent anticancer activities.

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Fig. 6

New N-4-methoxybenzoyl-N’-(4-fluorophenyl) thiourea 88 with excellent anticancer activities.

N-4-methoxybenzoyl-N^′-(4-fluorophenyl) thiourea, 88 was synthesized and screened for their anticancer activity. This compound shows less cell proliferation at low concentrations compared to hydroxyurea. IC₅₀ values were calculated for N-4-methoxybenzoyl-N’-(4-fluorophenyl) thiourea (0.720±0.07 mM) and hydroxyurea (16.535±2.092 mM) to ensure activity levels. The enhanced electronic, steric, and lipophilic properties of N-4-methoxybenzoyl-N’-(4-fluorophenyl)thiourea contribute to its activity. The lipophilic property can increase penetration through the membrane, enhance drug-receptor interaction, and enhance the compound’s biological activity. The electronic property of methoxy moiety contributes to the drug-receptor interaction. The presence of oxygen at methoxy can enhance the solubility in the blood (containing 70% of water); thus, it can be easily distributed. Last, steric property strengthened drug-receptor interaction so that it would prolong its activity with a rigid structure. Consequently, it was concluded that N-4-methoxybenzoyl-N^′-(4-fluorophenyl)thiourea has an excellent cytotoxic activity compared to hydroxyurea [49].

New thiourea derivatives 89–96 (Fig. 7) were designed and synthesized. Their cytotoxic effects have been screened against three cancer cell lines using SRB assay; HepG2, MCF-7, and HCT116. Most compounds showed significant antitumor activity of most compounds was investigated, while some exhibited outstanding results higher than the reference drug. Compound 961,1^′-(1,4-phenylene)bis(3-(benzo[d][1,3, 1,3]dioxol-5-yl)thiourea) have different IC₅₀ values for three cell lines such as (HepG2 = 2.38μM), (HCT116 = 1.54μM), and (MCF7 = 4.52μM). However, the standard drug doxorubicin has an IC₅₀ value of 7.46, 8.29, and 4.56μM. Remarkably, a non-cytotoxic effect of these compounds was reported against the normal tested cell line (IC₅₀ = >150μM). The results of cell cycle analysis showed that all tested compounds firmly arrest the cells at the Pre-G1 phase and also encouraged apoptosis at the G2-M phase [50].

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Fig. 7

Novel thiourea derivatives 89–96 with excellent anticancer activities.

The compounds 97–104 (Fig. 8) were synthesized, and anticancer activity was performed against various cell lines; HeLa, K562, MDA-MB-231, MCF-7, HEK293, and HepG2 through MTT colorimetric assay. Compound 99 with a 4-methoxyphenyl ring showed potent inhibitory activity, while in 98, the replacement of substituent with 3-methoxyphenylhenyl causes a reduction in the activity. Compound 97 with the 4-methyl phenyl group showed lower anticancer activity. The 3-fluoro phenyl ring on product 101 showed more potent inhibitory activity against all cancer cell lines than compound 102 bearing the 4-fluorophenyl ring [51].

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Fig. 8

Thiourea derivatives 97–104 with excellent anticancer activities.

Two series of bis-thioureas such as apara-series 105–111 and ameta-series 112–118 (Fig. 9) was synthesized and evaluated for their anticancer activities against various human cancer cell lines; A549 (lung carcinoma), HuCCA-1 (cholangiocarcinoma), MOLT-3 (lymphoblastic leukemia), and HepG2 (hepatocellular carcinoma). The evaluation of these compounds was performed against the Vero cell line, and their selective index was further calculated. Among para derivatives 105–111, compound 105 with methyl substituent showed cytotoxic activity against HuCCA-1 withIC₅₀ of 82.83μM and HepG2 with IC₅₀ of 21.67μM. The methyl group was replaced with chloro, bromo, and methoxy substituents resulting in loss of total cytotoxicity. Meanwhile, in the synthesis of compounds 109 and 110, the methyl group was replaced from compound 105 with nitro and trifluoromethyl moieties which displayed inhibitory efficiency against MOLT-3 and HepG2 cell lines. The addition of two trifluoromethyl groups on the phenyl ring over analog 111 provided a wide range of anticancer activity for all of the tested cells in a different range (IC₅₀ = 2.49–30.95μM) and selective index(SI = 2.29–28.44). The derivatives 105, 110, and 111 act as more effective anticancer agents against HepG2 cells than etoposide’s reference drug. Compounds 112–118 exhibited sufficient cytotoxicity against cancer cell line (MOLT-3) (IC₅₀ = 1.55–32.22μM). Methyl compound 112 (IC₅₀ = 13.90μM) and methoxy analog 113 (IC₅₀ = 32.32μM) have selectively inhibited the MOLT-3 cell line. The cytotoxic activity was increased against MOLT-3 and HepG2 cells due to halogen substituents in compounds 114 and 115. Moreover, the HuCCA-1 cell line was also inhibited by chloro analog 114 (IC₅₀ = 30.22μM). Their substitution with ED groups (R = CF3 and NO2) in compounds 116–118 increased the potency of inhibition against all cancer cells. Similarly, trifluoromethyl analog 17 was reported as the most effective compound against MOLT-3 (IC₅₀ = 1.55μM) and HuCCA-1 (IC₅₀ = 14.47). Furthermore, compound 118 showed significant activity against A549 (IC₅₀ = 16.67μM) and HepG2 cells (IC₅₀ = 11.50μM). The safety profile of derivative 118 was the most encouraging with selective index (SI = 1.64–20.60). Remarkably, derivatives 114 and 116–118 have displayed more potent anticancer activity against HepG2 cells than the etoposide. However, the most potent cytotoxic agent against HepG2 was compound 118 (SI = 20.60). It showed higher potency of 17.4-fold compared to etoposide and lower potency of 2.6-fold compared to doxorubicin. The evidence indicated that highly active meta analogs were R = NO2, CF3, and diCF3 compared to the corresponding para-counterparts as detected in compounds 116 > 109, 117 > 110, and 118 > 111 [52].

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Fig. 9

Two sets of bis-thioureas including a para series 105–111 and a metaseries 112–118 with excellent anticancer activities.

In MTT colorimetric assay, the anticancer activity of thiourea derivatives 119–128 (Fig. 10) was evaluated against HEK293, MCF-7, and HT-29 cell lines doxorubicin as the reference standard. The cytotoxic activities of all tested compounds were moderate to excellent against all tested cell lines. The anticancer activities of compounds 123 and 124 were more potent. The replacement of pyrimidyl-2-yl ring with 2-isopropyl (7c and 7d), causes a reduction of activity. The presence of phenyl ring on compound 120 (X = N) showed higher activity against MCF-7 and HT-29 as compared to compound 119 (X = C). Low cellular inhibitory activities were being reported after the addition of fluoro on pyridin-2-yl ring 117, 118 than pyridine-2-yl scaffold where no substitution occurred in 125 and 126. The presence of pyrimidin-2-yl moiety in compounds 124 and 123 increased inhibitory activity against HT-29 and MCF-7 cell lines (IC₅₀ = 5.28μM, 3.57 and 2.18μM). The inhibitory activity of compounds 124 and 123 to PI3Kwasexcellentthan reference compound LY294002 (IC₅₀ = 1.43μM). Furthermore, compound 124 has shown a significant selectivity and affinity to PI3K, indicating a decrease in potential toxicity against normal cell lines. The test of all synthesized compounds was performed against noncancerous HEK293 cells and was evidenced to be safe against normal cells [53].

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Fig. 10

Thiourea derivatives 119–128 with excellent anticancer activities.

Novel dipeptide thiourea derivative 129 (Fig. 11) was designed and synthesized. The synthesized compound was screened for its anticancer activities against various cancer cell lines. Further screening of antitumor activity has shown that few compounds displayed excellent inhibitory activity compared to the commercial anticancer drug Ube and 5-Fu. In particular, compound 129 (IC₅₀ = 4.85±1.44μM) has shown outstanding potency against the NCI-H460 as compared to Ube and 5-Fu. The simultaneous molecular mechanism studies have confirmed that compound 129 encourages apoptosis in NCI-H460 cells using the introduction of ER stress-reactive oxygen species.

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Fig. 11

A novel dipeptide thiourea derivative 129 with potent anticancer activities.

Moreover, cell cycle analysis showed that compound 129 halted the NCI-H460 in the S phase, further inducing apoptosis [54]. A novel series of [1,2,3, 1,2,3]triazolo[4,5-d, 4,5-d]pyrimidine/thiourea hybrids 130–147 (Fig. 12) were screened for theirantiproliferative activityagainst EC-109 H1650 GES-1, A549, MKN-45, and MGC803. Mostly, preference was given to the N-heterocyclic aryl group over the phenyl ring for the activity. The presence of 2-pyridyl and 3-pyridyl groups on compounds 139 and 140 have shown sufficient potency (IC₅₀ < 12μM) compared to the other compounds. Compound 140 for EC-109, A549,and H1650 cells exhibited antiproliferative activity compared to 5-FU (IC₅₀ = 4.99, 8.23, 2.38μM). Similarly, compound 142 with the aliphatic benzyl group showed less activity than compounds 139, 140, and 5-FU. However, they were more potent than compounds 130–138 with aryl groups. Compound 142 was less potent than other synthesized compounds and had zero activity against H1650. However, compounds 130–138 and 141 with the aryl group displayed weak to moderate anticancer activities. Furthermore, compounds 130–142 showed moderate to weak inhibition than 5-FU toward normal (GES-1) cell lines with less toxic compounds. The presence of the terminal indole group with compound 147 displayed excellent activity against tall te tested cell lines and showed sufficient potency compared to 5-FU for A549, MGC-803, H1650, and MKN-45 cells. The probable toxicity of compound 147 was preliminarily observed due to their adequate potency (IC₅₀ < 10μM). Compound 147 moderately inhibited the growth of normal human gastric epithelial cell line GES-1 (hillslope = 1.136, IC₅₀ = 27.43μM), whereas it potentially inhibited the H1650 cell growth (hillslope = 0.813, IC₅₀ = 1.91μM,), display a low toxicity and moderate selectivity. Mechanistic studies of compound 147 have potentially inhibited the formation of the colony on (H1650 cells) which further encouraged the apoptosis using intrinsic apoptotic pathways and arrested the cell cycle at the G2/M phase. Overall, studies have shown that these have remarkable activity against tested cell lines and are extremely useful for designing novel antitumor agents [55]. A series of thiourea derivatives 148–159 (Fig. 13) were synthesized and their cytotoxic activity was evaluated against HK-1, nasopharyngeal carcinoma (NPC) cell lines. All compounds except 148, 150, 151, 154, 155, and 157 have shown excellent activities against HK1 (IC₅₀ =≤μM).

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Fig. 12

Novel thiourea derivatives 130–147 with significant anticancer activities.

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Fig. 13

Halogenated thiourea aspirin (a natural product derivative 148–159 with significant anticancer activities.

Halogen-containing compounds (other than bromine) exerted in thiourea moieties at the meta position exhibited outstanding activities (IC₅₀≤8.0 mM) by comparing with ortho and para positions. It has been reported that the substitute of the compound at meta position was highly selective upon binding with a specific protein and has excellent activities to affect the function of cell’s survival. In compound 158, the presence of iodine at meta position exhibited the highly effective cytotoxic activity against HK1 among the tested derivatives of aspirin (IC₅₀ = 4.7μM). The presence of halogens in thiourea moieties at the ortho position has exhibited prominently reduction in cytotoxicity (IC₅₀ 10.8 to 13.9μM) (P < 0.05) by comparing with meta and para positions. The addition of bromine in compound 156 at the para position has shown outstanding cytotoxicity (IC₅₀ = 5.7μM). According to the IC₅₀ value, it was concluded that the presence of iodine, chlorine, and bromine at meta and para position of the phenyl ring has significantly increased the cytotoxicity profiles against HK1, NPC cells (P < 0.05). In the MTS assay, the treatment of HK1 with numerous concentrations of ATX 11 for 7 hours was performed to investigate the cell viability of NPC cells. The presence of thiourea moiety compared to the aspirin in the molecular structure has revealed significant functional groups for outstanding anticancer activity. The presence of a high electronegative sulfur atom was incorporated with protein through hydrogen bonding in the cancer cell and thus inhibited the growth of cells [56].

The novel synthesis of fluorinated thiourea derivatives having sulfonamide moieties 160–168 (Fig. 14) were synthesized. In colorimetric MTT assay, the inhibitory activity of the synthesized compounds was examined and compared to the familiar anticancer standard drugs (5-fourouracil and cisplatin) with similar conditions. The results confirmed that all compounds were tested which possess inhibitory activity to the tumor cell lines in a concentration-dependent manner. Furthermore, results revealed that compound 165 had the highest activity against the liver carcinoma cell line (HepG2), displaying stronger activity than the reference drugs (IC₅₀ = 4.8μg/mL), cisplatin (IC₅₀ = 18.8μg/mL), and 5-fourouracil (IC₅₀ = 4.9μg/mL). Compound 162 has shown excellent antitumor activity against the liver carcinoma cell line (HepG2). Their activity is mostly similar to cisplatin, followed by 166, 167, 163, and 160. However, tested compounds have shown less capability in inhibiting breast carcinoma cells as investigated before for liver carcinoma and against carcinoma cell line (MCF-7). The activity order was 165, 162, 166, and 167, respectively. In addition, compounds 160, 163, 164, and 168 showed the lowest activity among their analogues against the two tumor cell lines [57].

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Fig. 14

Fluorinated thiourea derivatives carrying sulfonamide moieties 160–168 with excellent anticancer activities.

Novel thiourea derivatives 169 and 170 (Fig. 15) were synthesized, and their structure was confirmed using spectroscopic techniques; ¹H NMR, FT-IR, HRMS, ¹³C NMR, and elemental analysis. These compounds have been tested for anticancer activity against prostate cancer (PC) cell lines: PC-3, LNCaP, and DU 145. Since compound 169 exhibited the highest cytotoxic activity, its IC₅₀ concentrations were further examined in cell cycle distributions of PC cell lines, colony-forming ability, morphology, fragmented DNA, RNA expression. Total collected data showed that treatment with compound 169 encourages DNA fragmentation and apoptosis in PC cell lines prevents cell cycle progression that leads to cell accumulation in either the S or G1 phases [58].

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Fig. 15

Novel thiourea derivatives 169, 170 with excellent anticancer activities.

N-substituted hydroxynapthaleneimino-oxindole derivatives 171–177 (Fig. 16) were known key inhibitors of PI3K, and their function is to regulate the programmed cell death or apoptosis. The most potent activities were observed in compounds 173, 174, and 176. The percentage of inhibition for anticancer activity was PI = 78.22±1.02 (173), 78.98±1.08 (176) and inhibitory concentration of IC₅₀ = 2.02±0.92μM (173), 1.98±0.18μM (176). However, two compounds, 171 and 177, were inactive for both activities while the remaining have shown moderate activity. Docking of compounds 171–177 was performed in the active site of PI3Ks p110α (PDB ID: 2ENQ) to obtain more information about inhibitor binding affinity and binding mode. The results showed that the hydrophobic interactions in the binding pockets of PI3Ks overcome the affinity of the most promising binding ligands (173 and 176 inhibitory constant (ki) = 102.4 nM and 128.23 nM). SAR study in terms of antiproliferative activity showed a substantial enhancement in the efficacy of N-substituted hydroxynapthaleneiminooxindole derivatives 171–177. Previously, their substitution has occurred at C2-position (R2) with a bulky group. The IC₅₀±SD = 1.98±0.18μM of compound 176 substitution has occurred with oxindole against MCF-7 cell lines with the most potent moiety and similarly active as DOX (IC₅₀±SD = 1.88±0.64μM), the standard. Compound 175 (IC₅₀±SD = 66.46±2.43μM) at R2 (–H) exhibited moderate activity among every (C2) substituted compound. The substitution of compounds 171 and 177 have occurred with –H, N2O, while it was found less active at R1. IC₅₀-based study of SAR has confirmed that compounds 173 and 176 were found most compelling and further investigated that a proper degree of electron density on the isatin ring was necessary to maintain the activity of compounds 171–177 [59].

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Fig. 16

N-substituted hydroxynapthaleneimino-oxindolethiourea derivatives 171–177 with excellent anticancer activities.

2-amino-4-substituted pyridine compounds were used to synthesize thiourea derivatives 178–181 (Fig. 17). Mass spectral data and elemental analysis, ¹H-NMR, FT-IR, ¹³C-NMR, were used to characterize the synthesized compounds. The fully characterized compounds were screened for anticancer activity against human osteosarcoma cell line, SJSA1 human lung cancer cell line A549, human colon cancer cell line HT-29, human prostate cancer cell line PC-3, human breast cancer cell line MCF-7} human cervical carcinoma cell line (HeLa), human chronic myeloid leukemia cell line K562 and cytotoxicity results against mouse fibroblast cell line NIH3T3. The compound 181 was identified as the most active with inhibitory activities of 38.92% and 35.96% inSJSA1 and HT-29 cell lines. The survival rate of 181 was high (92.01%) and non-toxic to NIH3T3 mouse fibroblast cells. Another significant inhibition was investigated in compounds 181 (32.29% inhibition vs. HT29) and 6 (35.82% inhibition vs. HeLa) at 10μM dose. These compounds were found to be safe for NIH3T3 fibroblasts [60].

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Fig. 17

Thiourea derivatives 179–181 with significant anticancer activities.

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Fig. 18

New diarylthiourea derivatives 182–184 with potent anticancer activities.

Three newly diarylthioureaderivatives 182–184 were synthesized. The anticancer activities of these compounds were screened against SkBr3 and MCF-7 cancer cells. These compounds exhibited 65–79% selective anti-proliferative activity against SkBr3 and MCF-7. The compound 183 has an IC₅₀ value of (MCF-7 = 1.3±0.009) and (SkBR3 = 0.73±0.03μM). MD simulations and Molecular docking were performed, and their binding free energies were calculated. A strong hydrogen bond of pi-pi stacking interactions with the vital residues; Phe864 and Thr862 were formed in compounds 182–184. 3DQSAR model has provided evidence regarding the key role of 4-chloro substituent of the phenyl ring and 3-bromo substituent of pyridine ring in the activity of the compounds [61].

Cancer is a persistent threat to the health of every individual and the second most familiar cause of death across the world. Researchers are continuously working in this direction to find a perfect way to strengthen the treatment approach. Significant progress in this field has been achieved by the rational design of thiourea-based compounds, targeting a specific protein/receptor/enzyme. In this regard, several thioureas derivatives were synthesized and further reported for their cytotoxic activity in recent years. Many of these derivatives with specific receptors showed remarkable anticancer activity and selectivity with less toxicity. Many thioureas containing drug candidates with excellent efficacy and suitable pharmacological profile are under clinical evaluation. Thus, it is clear from the above discussion that thiourea-bearing compounds present significant applications in drug development for treatment against different types of cancers. Despite remarkable advancements of thiourea derivatives, still, some research endeavors are requisite; (a) Designing of simple and green synthetic routes for novel, potent, and highly effective thiourea containing compounds. (b) A detailed study on pharmacokinetic and pharmacodynamic properties of potent thiourea derivatives for anticancer activities against different types of cancers. (c) To isolate and identify the naturally occurring thiourea-bearing compounds from plant and marine sources.