Thiourea Derivatives in Drug Design and Medicinal Chemistry: A Short Review

Thioureas have great medicinal applications as well as non-medicinal activities in industry, analytical chemistry and metallurgy. This review is a glimpse of methods of synthesis and applications of thioureas in the field of medicine and agriculture. Thioureas have a number of medicinal applications and a number of thioureas are in clinical use. Medicinal applications of thioureas are increasing with the passage of time. In the field of agriculture, thioureas are used as insect growth regulator, anti-fungal agents and herbicides.


Introduction of Thioureas
Thioureas is the class of the organic compounds having sulphur with the general formula (R 1 R 2 N)(R 3 R 4 N)C=S. These have structural resemblance to ureas, except that the oxygen atom of ureas is replaced by a sulfur atom; the chemical properties of urea and thiourea are quite different from each other.
Compounds produced from urea, isourea, or their derivatives by substituting sulfur by oxygen are named by adding a prefix thio before urea. S substituted thioureas are named as isothioureas. Thiourea system is numbered as below. [1] Following are some examples of thioureas with their names.

Types of Thioureas
Thioureas are classified into following categories on the basis of no. of substituent attached to thiourea moiety. Where R= phenyl, aryl, alkyl, cycloalkyl, hetrocycle, acyl etc.
Following are examples of mono N-substituted thioureas.

b) Disubstituted thioureas
These are either obtained if two H atoms of same NH 2 group are replaced by R 1 and R 2 or H of one NH 2 group is replaced by R 1 and H of other NH 2 group is replaced by R 2. Disubstituted thiourea are either 1, 1-disubstituted or 1, 3-disubstituted. There are some examples of these along with their general formula.
Where R 1 and R 2 = phenyl, aryl, alkyl, cycloalkyl, hetrocycle, acyl or any substituent. c) Trisubstituted thioureas Trisubstituted thioureas are obtained by replacing two H atoms of one amino group by R 1 , R 2 and one H atom of other amino group by R 3 . Trisubstituted thioureas are 1, 1, 3-trisubstituted. Their general formula is given below.

e) Guanyl thioureas
Guanyl thioureas are derivatives of guanidine having a common nitrogen atom between guanidine and thiourea moiety. [2] 3. General Methods for Synthesis (a) Thioureas from Isothiocynates Alkyl Isothiocynates 32 on reaction with primary and secondary amines 33 yield thiourea derivatives 34. [3] Where R 1 = alkyl, aryl or benzoyl. R 2 = alkyl or phenyl and R 3 = alkyl, phenyl or H. Where R 1 = R 2 = alkyl Scheme 2: General method for synthesis of Thiourea derivatives from Cyanamids.
(c) Thioureas from Thiophosgene In the presence of Pyridine, thioureas can be produced by condensing 37 and 39 with 38. (Scheme 3) If a single amine is used symmetrical thioureas will obtain (R 1 NH-CS-NHR 1 ). A mixture of thioureas will produce that can be separated by chromatography on using mixture of amines. [5] The composition will be as Where R 1 =R 2 =alkyl or aryl.

Application of Thiourea Derivatives
Thioureas have a variety of applications in different fields of life. Some of these are discussed below.

Application in Agriculture
Thioureas have versatile application in field of agriculture. These are used as to control the growth of insects, effect plant growth and seed germination, as fungicide and herbicide. 49 (thiourera derivative) control the growth of insects by destroying nymph at a conc. less than 1 ppm. This is environment friendly because don't destroy beneficial insects. [8] b) Effect on seed germination and plant growth Many organic compounds effect the germination and growth of seed. 50 effects elongation of roots of linseed. Elongation of root is decreased up to 50% at conc. 0.18 µ. At higher concentrations, on mustard tomatoes, ryegrass, lettuce and cress similar effects were observed. This compound has same effect as that of trifluralin. A study of analogues proved that this structural requirement is extremely specific for this activity. [9] Most of the compounds belonging to series of 51 showed plant growth regulating properties. [10] c) Antifungal Activity The chemicals or biological organisms that are used to kill fungus and fungal spores are called fungicide. Fungicides are very important in agriculture because fungus cause serious damage to crop. Thiourea derivatives 52, 53 and 54 are active fungicides. 52 and its p-chloro and p-nitro derivatives are most active ones. 55, 56 and their complexes show antifungal activity against the fungus yeast Saccharomyces cerevisiae and Penicillium digitatum. [11] Derivatives of 57 show significant antifungal and anti-viral activity of curative rates. [12].

d) Herbicidal Activity
58 and 59 show herbicidal activity against cucumber seedlings and former also showed activity against wheat seedlings. [13] 60 is effective against root and stalk of Amaranthus retroflexus L. [14]

Medicinal Applications of Thiourea Derivatives
Applications of thiourea derivatives in field of medicine can't be neglected. These are being used in all aspects of medicine. I. V. virus as well as these have spermicidal effect. But spermicidal activity of Novel derivatives is a function of time and concentration. [16] b) Thiourea derivatives as antioxidant The compounds that prevent the oxidation of other substances are referred as antioxidant. In these reactions electrons and hydrogen is transferred to oxidizing agent.
These can result in free radicals that can destroy cell.

74
(2-thiouracil), 75 (6-n-propylthiouracil), 76 (6-methylthiouracil), 77 (carbimazole), 78(methimazole), 79 (1, 3-diethylthiourea), and 80 (2-thiobarbituric acid). [21] g) Thiourea derivatives as anti-epileptic drugs Derivatives of 81a and 81b are active anti-convulsant with 50% effect dose of 1.72 and 1.19 mg/k.g respectively. [22] Where R 1 = C 7 H 13 , C 8 H 15 and R 2 = C 6 H 11 h) Thiourea derivatives as anti-hypertensive Mono and Disubstituted phenylthiourea act as anti-hypertensive compound. 82, 83, 84, 85 and 86 show anti-hypertensive activity but greatest activity was observed for 85. [23] i) Thioureas as rodenticide Thioureas are best rodenticides. 87 (Alphanaphthyl thiourea) and 88 (phenyl thiourea) are most commonly used rodenticide. Alphanaphthyl thiourea is especially active in brown rats. [24] j) Thiourea derivatives as anti-cancer drug Cancer is an alarming ailment; different types of cancers can be treated effectively, if diagnosed at start. The following are the methods applied for the treatment of cancer; organ transplantation, surgery, palliative care, biotherapy, chemotherapy and radiation therapy. [25] But commonly used are chemotherapy and radiation therapy. Mostly these are used in combination. Nature of disease decides the type of treatment. Every treatment has its own risks and benefits. Generally, chemotherapy is the most common method. [26] Chemotherapy is used for various types of cancers. Chemotherapy use medicines to kill the origin of cancer or kill cancer. Radiotherapy can easily be applied to cure tumors restricted to a small area. Radiotherapy can be applied internally and externally. The rate of Cure is diminished by metastasis in internal radiotherapy. In case of small tumors surgery and radiotherapy are approximately forty percent efficient. Due to metastasis of cancer cells sixty percent is still on its last legs. [27] Chemotherapy is less expensive than surgery and radiotherapy. Metastasized tumors can easily be treated by chemotherapy. [28] The anti-cancer drug eliminates cancerous cells without affecting the normal cells can be regarded as best one. In actual all anti cancer drugs destroy normal cells and have vomiting like side effects. In chemotherapy different drugs are used to slow down the cell cycle. Drug should slow down at least one stage of cell division to check cell division. Anti cancer drugs are classified into following categories i.e. alkylating agents, One of the most important applications of Thiourea derivatives is their anti-cancer activity. Many thioureas are being used as anti-cancer therapeutics and a lot of are in clinical trial. Because of genotoxicity and cytotoxicity to normal cells caused by anti-cancer drugs medical science is in search of novel and safer anti cancer agents. These side effects limit both their use and efficiency. Thioureas, ureas and benzothiazoles are the most active anti cancer drugs. Ureas and thioureas in combination with benzothiazoles produce DNA topoisomerase or HIV reverse transcriptase inhibitors. Novel thioureas having general formula 89 were prepared and screened for their anti-cancer activity using Hela cells and MCF-7. Most of tthiourea were efficient in cytotoxicity. [39] k) Thioureas as DNA binder
A series of some novel N3, N3'-bis-(disubstituted)isophthalyl-bis-(thioureas), with general formula [C6H4{CONHCSNR1R}2], where R 1 = H (a-d, f, g, i, j), C 6 H 5 (e), C 6 H 11 (h) and R 2 = C 5 H 4 N 3 (a), 4-C 6 H 4 COOH(b), 3-NO 2 C 6 H 4 (c), 2-NO 2 C 6 H 4 (d), C 6 H 5 (e), 2,4(CH 3 )2C 6 H 3 (f), C 6 H 11 (g, h), C 5 H 4 N(i), 3-NH 2 C 6 H 4 (j) have been prepared in good to excellent yields by reaction of isophthaloyl isothiocyanate with primary and secondary amines using dry acetone as solvent. These compounds were characterized by I. R, 1 H-NMR spectroscopy and elemental analysis. These novel compounds tested for Urease inhibition activity and anti-bacterial activity of six different stains. The compounds a, c and f exhibited potent activity against all tested bacteria with highest inhibition zones. The compound h also showed great anti bacterial activity. The compounds e, i and j were inactive and showed no inhibition against all bacteria. Ampicillin and ciprofloxacin were used as reference standard and activity was performed by using disc diffusion method. The results of urease inhibition were also appraisable. For Urease Inhibition activity Thiourea itself used as reference standard. Compounds b and c proved to be the most potent urease inhibitor showing an enzyme inhibition activity with an IC 50 value of 26.3 ± 0.5 µM and 26.7 ± 0.5 µM respectively. These values are comparable to 21.0 ± 0.1 µM of the standard thiourea. The compounds a and d also showed greater activity but compounds i and j showed no activity. [43]

Applications of Complexes of Thioureas
Thiourea derivatives have a great potential to act as ligand. Especially co-ordination chemistry of benzoyl thioureas satisfactorily explained. These form more stable complexes having six membered rings. These thioureas have capability to act as chelating agents because of the presence of C=S and C=O functional groups. That's why novel thioureas have attention researchers due to their property to act as ligand. [44] i). Biological properties Thioureas itself and their metal complexes show a number of biological properties such as anti-cancer, anti-microbial, anti-fungal etc. The compounds 97, 98 and 99 after complexation with Cu(II) show enhanced antibacterial activity against Staphylococcus aureus. [45] Thioureas those are complexed with metal via sulphur antifungal and antibacterial activities. Thioureas can co-ordinate to metals as neutral ligands and anionic ligands. There are multi-bonding possibilities of metals with thioureas due to presence of various donor atoms like N, S and O. Chelating thioureas that have S, N, and O Show a broader range of biological properties. 98 when complexed with Pt(II), Pd(II), Hg(II), Ni(II), Co(II), Zn(II), Mn(II) and Cd(II) showed significant anti-bacterial activity against Escherichia coli, Pseudomonas aeruginoses and Staphylococcusaureus. [46] 101 form stable complex with Ni (II), and Cu(II) that show antibacterial activity higher than corresponding ligands. [47] 102 ligand acts as monodentate ligand through the sulfur atom forming stable complexes with Co(II), Zn(II), Cu(II) and Fe(III). These compounds don't show conductivity indicate that there is no free ion in complexes. These complexes show considerable anti-bacterial activity against E. coli, P. auruginosa, K. pnemoniae, B. cereus, S. aureus, and B. pumilus. [48] Some novel thioureas N3, N3'-bis(disubstituted)isophthalyl-bis(thioureas) and N3, N3, N3', N3'-Tetrakis (disubstituted)isophthalyl-bis(thioureas) compounds with general formula [C6H4{CONHCSNR1R}2], where R1 = H (1-4), C6H11(5), C6H5(6) and R2 = 4-NO2C6H4(1), C6H11(2), 2,4(CH3)2C6H3(3), C5H4N(4), C6H11(5), C6H5(6), and their Cu(II) and Ni(II) complexes have been synthesized. All the synthesized compounds were characterized by I. R, 1 H-NMR spectroscopy and elemental analysis. These six ligands and their metal complexes were then tested for anti-bacterial activity. Ampicillin and ciprofloxacin were used as reference standard and activity was performed by using disc diffusion method. The antibacterial activity of ligands enhanced after complexation. The compounds 5 and 6 showed no activity against any stain except S. typhi. The compound 1 and their Ni and Cu complexes showed highest activity. [49] ii). As precursor of Metal Sulphides Nano Particle Metal complexes of thioureas as precursor of metal sulphide nano particles. Studies revealed that thiourea and its derivative that co-ordinate to M (II) cations via sulphur are good precursor of Metal sulphide nano particles. Stability of complexes was checked by thermogravimetric analysis and potential as precursor of metal sulphide thin film was estimated by chemical vapour depositiontechnique. 103, 104, 105 and 106 are precursor of sulphide nano particles. [50]

Conclusion
Thioureas are versatile chemicals with outstanding biological applications. These are used in agriculture, analytical industry, metallurgy, industry and in the field of medicine. Most prominent biological applications of Thioureas is for treatment of co-infection, as antioxidant, as ant allergens, as anti bacterial agents, as anti-inflammatory, as anti-thyroid drugs, as anti-epileptic drugs, as anti-hypertensive, as rodenticide, as anti-cancer drug, as DNA binder and as Urease Inhibitors. Complexes of thioureas are used as precursors and antibacterial agents. Thioureas act as precursor of gaunidines and hetrocyclic ring systems.