Organotin Compounds: Perspectives and Potential

Ashu Chaudhary"1 and R.V. Singhb

aDepartment of Chemistry, Banasthali Vidyapith University,Rajasthan-304022, India. E-mail: ashu chaudhary 77@yahoo. com b Department of Chemistry, University of Rajasthan, Jaipur-302 004, India.

ABSTRACT

This review concerns the developments on the biocidal properties of the organotin compounds with an emphasis on the authors' contribution to the field. The organotin compounds with a variety of nitrogen/ oxygen and sulfur donor ligands, developed mainly during the last decade, has been reviewed. The article is focused on the design, synthesis and biological perspective of organotin compounds. Particular attention has been paid to the effectiveness of these compounds as: insecticides, nematicides, antifertility agents and biocides.

CONTENTS 1. INTRODUCTION 1.1. Early Studies on Organotin Compounds 1.2. Aim and Structure of the Review 2. EXPERIMENTAL 2.1. Organotin Compounds with Schiff Bases 2.2. Heterobimetallic Organotin Complexes 2.3. Novel Chiral Organotin(IV) Complexes of Phenanthrolines/ Bipyridine 2.4. Unsymmetrical Macrocyclic Organotin Complexes 3. RESULTS AND DISCISSION 4. NEMATICIDAL ACTIVITY 4.1. Experimental 4.2. Observations 4.3. Mode of Action 5. INSECTICIDAL ACTIVITY 5.1. Significance and Historical Notes

'Author for correspondence: Dr. Ashu Chaudhary, Department of Chemistry, Banasthali Vidyapith University, Rajasthan- 304022, India. E.mail: ashu [email protected]: Fax : +91-1438-28365

107 Vol. 31, Nos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

5.2. Recent Developments 6. ANTIFERTILITY ACTIVITY 6.1 Background Information 6.2. Recent Developments 6.2.1. Diorganotin(IV) complexes of bibasic tridentate Nr,Nr,0 donor sulphonamide imine. 6.2.2. Triorganotin(iv) complexes of biflmctional tridentate hydrazinecarbodithioic acid 6.2.3. Organotin derivatives of benzothiazoline 6.2.4. Novel chiral organotin(IV) complexes of bipyridine 6.2.5. Unsymmetrical macrocyclic organotin complexes 6.2.5.1. Organotin complexes with bis(3-oxo-2-butylidene)propane-l,3-diamine (L) 6.2.5.2. Organotin complexes with bis bis(benzil) propylenediamine(L') 7. BIOCIDAL ACTIVITY 8. FUTURE PROSPECTS

1. INTRODUCTION

1.1. Early studies on organotin compounds :

Tin has been known to us for ages as the discovery, around 3500 BC, that copper can be hardened and strengthened by alloying with tin is generally marked as the advent of the Bronze Age 1-3. However, as a pure metal it was isolated in 800BC. Currently several tin complexes are important due to their pharmacalogical properties1"5 and industrial applications6"7. The chemical reactivity of organotin species and availability of a wide range of structural features in them have made the subject of organtin complexes a rich and diverse field of chemistry. The various aspects of organotin8'12 compounds reviewed in the last decade include polyhedron organotin compounds13 , bidentate oxygen donor complexes of tin14, chemistry and applications of organotin(IV) complexes of phosphorus-based acids14, organotin(IV) complexes of aminoacids and peptides16"19, chalcogenido metalates of the heavier group 14 elements20 and organostannates21, toxicity and health effects of organotin compounds22, toxicological review of organotin23, organotin compounds and their therapeutic potential24, organotin compounds in the environment25, organotin chemistry26. In the present review, we have focused the attention on the recent developments, perspectives and biopotential in the chemistry of organotin complexes with those nitrogen ligands, which were reviewed and continue to be a subject of interest. Moreover, the total number of organotin complexes as biocides known at present is fairly large. Therefore, we have attempted to present a critical overview of the present status of the subject rather than a comprehensive treatise. Consequently, the work done in the last 10-12 years is mainly emphasized. The use of some organometallics employed as biocides, i.e., insecticides, pesticides, fungicides, and herbicides and their possible short- as well as long-term effects on ecology and environment are attracting the attention of scientists and in many cases, arousing deep concern of society in general about the organometallics of two metals, mercury and tin, used extensively for their biocidal properties (the use of the

108 Chaudhary and Singh Main Group Metal Chemistry

former has been banned in many countries).7 The pronounced biological effects of organotin compounds led to their wide applications in fields like medicine and agriculture. The ever-increasing practical uses of organometallics as biocides in agriculture, as antiknock agents in automobiles and as catalytic agents in a number of industrial (especially biotechnological) processes have led to an increasing concern about their environmental aspects also.7

Cases et al.21 have reported the synthesis of diorganotin (IV) - promoted deamination of amino acids by pyridoxal: Pyridoxal 5' - phosphate, (PLP) and pyridoxal(PL) itself were reacted with diorganotin (IV)

derivatives in the presence and absence of aminoacids. With PLP the complexes [Sn R2 (PLP -2H)] [R=Me,

Et, B4] were isolated and characterized by EI and FAB mass spectrometry and by IR, Raman and Mossbauer spectroscopy. The positive findings of antibacterial activity of these compounds against Pseudomonas aeruginosea (ATCC 27853), Staphylococcus aureus, Bacillus subtilis, Escheriehia coli and a carbapenem- resistant P. aeruginosa strain have also been reported.

(1)

Ruisi and cowerkers28 have reported the synthesis and in vitro antimicrobial activity of organotin (IV) complexes with tri-azolo-pyrimidine ligands containing exocyclic oxygen atoms. In vitro anitimicrobial tests were reported on n-Bu3 S„ Ph3Sn(Htp02) and Ph3Sn(Htp02) and a good antifungal and antribiofilm was observed in particular for η Bu'3 Sn (Htp02). Organotin (IV) complexes of amino acids, and their organic derivatives containing the carboxylic O-Sn (IV) bond, display significant antitumor activity and promising potential in many other fields, like polymer chemistry, pesticidal and antibacterial agents.29"36 The structural chemistry of organotin (IV) complexes of carboxylic moieties as amino acids N-protected amino acids with a coordination number higher than four is being extensively studied because of their biological activity, enhanced reactivity and stereochemical non- rigidity.37'45 Several reports have been cited in the literature by other research groups pertaining to the bioactivity as anti-tumour agents and structural chemistry of di- as well as triorganotin (iv) compounds.37"49 Ashfag et al50 have reported in vitro LD50, antibacterial .antifungal and antiyeast bio-tests of organotin (IV) complexes of 2-maleimidoacetic acid, which proved them to be powerful biocides. The in vitro anti-tumour and analgesic activities also displayed excellent potential of the titled compounds.

109 Vol. 31, Nos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

Ο

R

/ \ Bu Bu

(2)

Farina51 and coworkers have reported the synthesis of organotin dithocarbamates derived from hydroxylated amines, which have been found to be biologically active. The coordination of Schiff base nitrogen with tin has been investigated in several systems. The complexes having the general structural formula (3) have been synthesized52"54, structurally characterized55 and studied for their condensation with aldehyde.56 The coordination geometry of tin in (3) is trigonal bipyramidal (Sn-N=2.135A°). Dinuclear tin complexes57 of tridentate dianionic Schiff base ligands,, have been synthesized by reacting moieties of the type (3) with diorganotin dichloride. These complexes speak for their spectacular progress in bioinorganic chemistry. An adduct of SnCl4 with a natural Schiff base (4), a possible intermediate in aziridination, has been structurally characterized58.

R R (3) (4)

Sousa and coworkers59"61 have synthesiyed Sn (IV) complexes of Schiff bases (5) to (14) (stoichiometry SnL2) by anodic oxidation of tin in their acetonitrile solution. Three of these complexes were characterized structurally, two of which were formed with the ligands derived from (R=5-Br) and a (R=H) and have tin in octahedral coordination geometry with facial occupancy. The third complex characterized structurally is of the ligand derived from (5) (R=4, 6-dimethoxy) and also has octahedrally coordinated tin with meridional ligand occupancy. The Sn-N bond length is between 2.123 and 2.23 A0 for all three structurally characterized complexes.

110 Ill Vol. 31, Nos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

(13) (14)

The SnCI4 and R3.xSnCl1+x (χ = 0 to 2;R= Me, Bu or Ph) have been reacted with Schiff bases (10) to (13) and the products characterized by spectroscopy, except the one formed by reacting Ph2SnCl2 with (ll)which was characterized by single crystal structure determination. The product obtained in this latter reaction is

Ph2Sn(13-2H). The generation of (11) from (13) has been ascribed to the concomitant C=N bond cleavage and C=N formation between amine Ν atom and exocyclic carbon of (ll).62 The Sn-N bond length is from 2.20(2) to 2.22 (2) A and coordination geometry of Sn is octahedral. The Ph groups are trans to each other, whereas both N/O donor atoms are cis to each other. The multidentate Schiff bases derived from salicylaldehyde and diamines are very versatile ligands. Their Sn(II) and Sn (IV) complexes have also received attention in the recent past.63'64 The reactions of Sn (IV) and organotin (IV) pseudohalides with 2-hydroxy-l-naphthalideneimine65'66l-[(4-methylphenelimino)methyl]-2 phenol give adducts. The crystal structure of Me2Sn (NCS)2 [HOC6H4CH=NC6H4CH3]2 suggests that this adduct has six-coordinated Sn, is a trans isomer and is formed through the OH group of each ligand. The Sn- NCS bond length is 2.270 A. The hydrazones, semi-and thio-semicarbazones are the ligands having the >C=N-NH-R, >C=N-NH- C(O)- NHR and >C=N=NH-C(S)-NHR groups respectively. Due to the presence of a >C=N- moiety like Schiff bases, they may be put in the same category. They can act as neutral as well as anionic donors. The tin complexes of these ligands have been investigated, in which they coordinate in both forms. The di-2- pyridylketone 2-aminobenzoylhydrazone (a) on reaction with Ph2SnCl2 forms Ph2SnCl2 (a), (b), and PhSnCl, (c)-H, (d), which are characterized structurally.67 In (b) the hydrazone ligand weakly coordinates through pyridyl and >C=N nitrogen atoms and Ο of >CO group, resulting in a heptacoordinated Sn (Sn-N =2.695(8)- 2.749(9) a), with four close and three distant (two Ν and O) atoms. The environment of the tin atom is highly irrregular and cannot be described by any idealized geometry. In (a), Sn is in distorted octahedral geometry (Sn-N=2.140(18)-2.162(19) A) and the deprotonated hydrazone ligand is more strongly bonded in comparison to (b)68 N-)2-[yridinylmethylene) respectively the first of which is characterized structurally.The reactions of Ph2SnCl2 with 2- furanthiocarboxyhydrazide (14), 4-hydroxyphenylthiocarboxhydrazide and salicylaldehyde-2-furanthiocarbo-xhydrazone have resulted in adducts There is also some current interest in tin complexes of acylhydrazines71·72, as organotin(IV) complexes of salicylaldehyde and N-pyridoxylidene acylhydrazines have been reported in the recent past also. The imidazole group is a biologically important molecule, as it plays an important role in enzymes like

112 Chaudhary and Singh Main Group Metal Chemistry

chyomotrypsin, creatine kinase and carboxypeptidase. Metal complexes of imidazole, benzimidazole and their derivatives have promising antitumor and antimicrobial activity73'74. The spectroscopic characterization of adducts of SnCl2 with imidazole and its derivatives like 1-methyl- 4-methyl-, and 1, 2- dimethyl-, has been reported even up to the late eighties75. In 1990 Vasnin et al.76. reported the crystal structure of adducts of the type [SnCl2.L2] (where L =1-vinyl and 1-benzylimidazole). [Me2SnCl2) imidazole)] has been synthesized in aqueous and non-aqueous solvent77,78. The Sn is octahedrally coordinated and the structures are all-trans isomer (Sn-N=2.312(2) A).The nitrogen of the imidazole ring is intermolecularly hydrogen-bonded to chlorine atoms. [Ph2SnCl2 (imidazole)] has been reported. The several imidazole derivatives studied for their ligation with tin (IV) are : 1-methylimidazole79, 4-phenylimidazole80, 2-methyl-, 2-isopropyl and 4-methyl- imidazole81, imidazoline-2(l, 3H)-thione, 2-phenylimidazole, 1-acetylimidazole and 1-methylimidazoline- 82 83 2(3H)-thione , imidazole-4-acetic acid . They have been reacted with RnSnX4 .„ (n— 0 to 3; R— Me. Et, n- Bu, Ph, Cy; X= halide) type of species to form a variety of complexes, which have been subjected to halide substitution reactions to further generate new complexes.

84,85 The tetrazole-containing organotin derivatives(15) have been synthesized by reacting Bu3SnN3 with

Ph3Sn(CH2)3 CN at 140 °C for 3h: further heating of 15 for 21 h results in a bicyclic organotin heterocyle (16). The single crystal structure of (12) has been determined. The bis (organotin tetrazoles) (17) and (18) have been synthesized by the compounds of the type 19 and showed that they form a two-or three-dimensional supramolecular array, the arrangements of which are dictated by organic groups on Sn, which has a five-coordinate (trigonal dipyramidal) geometry with Ν donors in axial position. The structure of 17 when R= n-Bu and n=6 has a unique bilayer arrangement with 40-and 58-membered rings which generate channels through the lattice array in all three dimensions. Reactions similar to those used in the synthesis of 15 to 18 have been suitable to synthesize tris(triorganostannylterazole) and tetrakis (triorganostannyltetrazoles) (representative examples : (19) and

SnPh3 Ph2 (15) (16)

R3Sn R3Sn R3Sn R3Sn (17) (18)

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•SnR3

r3s R3Sn SnR3 (19) (20)

The pyridine derivatives are known to be widely explored ligands. The complexes of a variety of tin species with such ligands have been explored during the last decade. The spirocyclic bis(ethane-l,2- dithiolato[2-]S,S') tin (IV) forms hexa-coordinated crystalline complexes with pyridine and 2-(2- pyridyl)ethylamine, which were characterized structurally and found to be trans isomer91. The reactions of

R2SnO with picolinic acid (pic) and picolinic acid N-oxide(picO) in different molar ratios have resulted in several complexes of diorganotin species with these ligands (stoichiometrics : [R2Sn(pic/picO)2], but none of them is structurally characterized92. The single crystal structure of dicyclohexyltin(IV)bis(2-pyridylthiolate), determined by X-ray diffraction, reveals that Sn has distorted octahedral geometry due to two weak interactions with pyridyl nitrogen (Sn-N=2.72 A), which are cis to each other. The two cyclohexyl groups are trans to each other. The Sn (IV) complexes of pyridine-2-carboxylic acid, of stoichiometry RSn(C6H4N-2-

COO)3 H20, have been synthesized but characterized by spectroscopic methods only. However, 93 [Me2Sn(C6H4N-2-C00)(H20)] is characterized structurally . A variety of RSnX3, R2SnX2 and R3SnX compounds have been reacted with 8-hydroxyquinoline (oxin) and its [R3Sn(oxin/txin)] have been synthesized94,95. They are characterized by 'H, 13C and U9Sn NMR in solution and solid state 119Sn Cp-MAS NMR spectra in some cases. Several adducts of tin(IV) and organotin(IV)with 2,2'-azopyridine and 2-arylazopyridine have been synthesized, but the crystal structure of probably [Me2SnBr2(2,2'-azopyridine)] only has been reported in the last decade96'97. The tin atom is seven-coordinated and the geometry is close to distorted pentagonal bipyramidal with Br and Ν in the axial positions. The adducts of di-and triorganotin halides/perchlorated with 2,2'-bipyridine (bipy) and 1, 10- phenanthroline (phen) were synthesized and mostly characterized by spectroscopic method98·99. [n-BuSnCI

(S(Ch2)2S) (phen)] is structurally characterized.

The l-Sn-2, 4-(SiMe3)2-2,4-C2B4H4 and l-Sn-2-(SiMe3)24-(Me)-2,4-C2B4H4 react with 2.2'- bipyridine, 2,2'- bipyrimidine, (ferrocenylmethy)-N, N-dimethylamine and 2,2':6',2'-terpytidine to form adducts. The single crystal structures of the adducts of first closo-stannacarboranes with the first three nitrogen donor are reported.100 The pyrazine adducts of organotin species have been under investigation since 1967101. However, during the last decade the formation of adduct between Ph2SnX2 and R2 SnX2 (X =Ci,Br, I; R= Me, Et, N-pr, n- Bu) and pyraizine has been explored in acetonitrile of chloroform solution by 119 Sn NMR spectroscopy102'103.

114 Chaudhary and Singh Main Group Metal Chemistry

Only 1:1 and /or 1:2 adducts are formed. The equilibrium constants are reported. The [Ph2SnCl2bipym] (bipym =2,2', 6,6'-bipyromidine) is characterized structurally and has octahedrally coordinated Sn. The two phenyl groups are trans to each other. A large number of organo-tin compounds have been used as fungicides, algacides, herbicides and pesticides in agriculture. In spite of the considerable amount of work on the fungitoxicity of organometallics say organotin compounds, knowledge in this direction continues to be rather empirical. For example, while comparing the toxicity of a large number of mixed trialkyl tin acetates, R R' R" Sn (OOCCH3), it has been shown that irrespective of the actual R, R', and R" groups present, the toxicity reaches a maximum when the total number of carbon atoms in all three alkyl groups together are 9 to 12.104 In spite of the reservations arising due to actual as well as potential environmental pollution, a wide variety of organometallic compounds are finding increasing uses as pesticides. For example, tri-phenyl tin hydroxide and acetate are both used in numerous formulations for the control of a variety of fungal growths, particularly potato blight. Tricyclohexyltin hydroxide is a very effective acaricide for controlling fruit free red spider mite on apples and pears. Besides, these organotin compounds have been used as antifouling agents, i.e., in protecting various surfaces like that of wood from the growth of mould. The series of organotins, (n-C4H9)3 Sn CH2R (where R is a quaternized amino group) showed herbicidal activity with no phyto-toxicity. n-Tri-butyl tin fluoride was shown to be selective in controlling weeds without damage to 104 corn or rice. The existence of a tin cycle has been investigated extensively since the 1970's in view of the larger quantities of organotins entering the environment through their increasing applications as pesticides. A number of pathways, e.g., oxidative methylation of tin(II), environmental methylation of tin and biomethylation of stannic oxide and trimethyltin hydroxide by sediment microorganisms have been suggested in this direction.105 Tin forms a number of organometallic compounds in which tin exists in both Sn(II) and Sn(IV) states. Many organo-tin compounds are used as agriculture biocides to protect the crops from fungi, bacteria, insects and weeds. The great advantage of organotin compounds in these applications is that they are nontoxic to mammalians.107 Organotin(IV) compounds are a widely studied class of metal-based antitumour drugs. Their intensive investigation has led to the discovery of compounds with excellent in vitro antitumour activity, but, in many cases, disappointingly low in vivo potency or high in vivo toxicity.41'42 The design of improved organotin(IV) antitumour agents is unfortunately hampered by the paucity of information concerning the cellular targets of these compounds and their mechanism of action, although inhibition of mitochondrial oxidative phosphorylation appears to be an important mode of toxicity.107 + Mono-organotin(IV) compounds, considered the least toxic among organotin(IV) derivatives (R3Sn(IV) 2+ 3+ 4+ > R2Sn(IV) > R Sn (IV) > Sn on the toxicity scale), have not achieved as much commercial applications as diorgano- and triorganotin(IV) derivatives. However, they are often used as hydrophobic agents for building materials and cellulosic matter and can be present in the aquatic environment as the first step in the alkylation of inorganic Sn.108

115 Vol. 31, Νos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

Attempts to improve the bioactivity of the organotin(IV) cations by the formation of water-soluble complexes or by their inclusion into ß-cyclodextrin have also been reported. In spite of their wide-spread activity, these antitumour organotin(IV) complexes, have not yet been subjected to extensive clinical trials in humans.107

1.2. Aim and Structure of the Review:

In the present article special attention is devoted to the most recent progress made in the synthetic procedures for the organotin compounds and their biological relevance. It can be divided into four parts. The first part, containing the sections 2 and 3, concerns the synthesis and spectroscopic characterization of organotin complexes. The particular sections, 4 to 6, are devoted to the biopotentialities of these complexes. So far, focus has centered on nematicidal, insecticidal and antifertility activities of these compounds.

2. EXPERIMENTAL

2.1 Organotin compounds with Schiff bases :

The ligands used are: 2-Acetylfuransulphathiazole(2-Ac-F-StH), 2-Acetylfuransulphapyridine(2-Ac-F-SpH), 2-Acetylfuransulphaguanidine(2-Ac-F-SgH), 2-Acetylnaphthalenesulphathiazole(2-Ac-N-StH), 2-Acetylnaphthalenesulphapyridine(2-Ac-N-SpH), 2-AcetylnaphthaIene-sulpha-guanidine (2-Ac-N-SgH),

Salicylanilidesulphathiazole(SaH-A-StH), Salicylanilide-S-Benzylditithiocarbzate (Sal. Benzh2), ί'Η, L2H, Bis(3-oxo-2-butylidene)propane-l,3-diamine (L) and bis(benzil) propylenediamine(L'). The following complexes have been synthesized during the course of our present investigations on organotin complexes109"117.

2.1.1. Triorganotin(IV) complexes of monobasic bidentate sulpha η amide imines of heterocyclic ketones.

1. Ph3Sn (2-Ac-F-St): Peach solid, M.p. 81-83 °C

2. Ph3Sn (2-Ac-F-Sp): Peach solid, M.p. 74-76 °C

3. Ph3Sn (2-Ac-F-Sg): Cream solid, M.p. 81-83 °C

4. Ph3Sn (2-Ac-N-St): Light brown solid, M.p. 134-136 °C

5. Ph3Sn (2-Ac-N-Sp): White solid, M.p. 85-87 °C

6. Ph3Sn (2-Ac-N-Sg): White solid, M.p. 94-96 °C

2.1.2. Triorganotin(IV) complexes ofbibasic tridentate sulphonamide imine of anilide

7. Ph3Sn (SaH-A-St): Cream solid, M.p. 103-105 °C

2.1.3. Diorganotin(IV) complexes of monobasic bidentate 7V~VV donor ketimines.

8. Me2SnCl (2-Ac-F-St): Brown solid, M.p. 138-140 °C

116 Chaudhary and Singh Main Group Metal Chemistry

9. Me2Sn(2-Ac-F-St)2: Dark brown solid, M.p.189-191 °C

10. Me2SnCl(2-Ac-F-Sp): Peach solid, M.p.164-166 °C

11. Me2Sn(2-Ac-F-Sp)2: Brown solid, M.p. 149-151 °C

12. Me2SnCl(2-Ac-F- Sg): Brown solid, M.p.219-221 °C

13. Me2Sn(2-Ac-F- Sg)2: Peach solid, M.p. 134-136 °C

14. Me2SnCl(2-Ac-N-St): Light-yellow solid, M.p. 119-121 °C

15. Me2Sn(2-Ac-N-St)2. Light-brown solid, M.p.91 -93 °C

16. Me2SnCl(2-Ac-N-Sp): Yellow solid, M.p.154-156 °C

17. Me2Sn(2-Ac-N-Sp)2: Cream solid, M.p. 144-146 °C

18. Me2SnCl(2-Ac-N-Sg): Light-peach solid, M.p.170-172 °C

19. Me2Sn(2-Ac-N-Sg)2: Off-white solid, M.p.138-140 °C

20. Bu'2SnCl (2-Ac-F-St): Cream solid, M.p.85-87 °C

21. Bu'2Sn(2-Ac-F-St)2: Cream solid, M.p. 144-146 °C

22. Bu'2SnCl(2-Ac-F-Sp): Yellow solid, M.p.122-124 °C

23. Bu'2Sn(2-Ac-F-Sp)2: Yellow solid, M.p. 131-133 °C

24. Bu'2SnCl(2-Ac-F- Sg): Cream solid, M.p. 140-142 °C

25. Bu'2Sn(2-Ac-F- Sg)2: Light yellow solid, M.p. 144-146 °C

26. Bu'2Me2SnCl(2-Ac-N-St): Cream solid, M.p. 155-157 °C

27. Bu'2Sn(2-Ac-N-St)2: Off-white solid, M.p.132-134 °C

28. Bu'2SnCl(2-Ac-N-Sp): Off-white solid, M.p. 137-39 °C

29. Bu'2Sn(2-Ac-N-Sp)2: White solid, M.p. 143-145 °C

30. Bu'2SnCl(2-Ac-N-Sg): Off-white solid, M.p.138-140 °C

31. Bu'2Sn(2-Ac-N-Sg)2: White solid, M.p. 131-132 °C

32. Ph2SnCl (2-Ac-F-St): Cream solid, M.p.154-156 °C

33. Ph2Sn(2-Ac-F-St)2. Brown solid, M.p.137-139 °C

34. Ph2SnCl(2-Ac-F-Sp): Brown solid, M.p.l 13-115 °C

35. Ph2Sn(2-Ac-F-Sp)2: Yellowish solid, M.p. 145-147 °C

36. Ph2SnCl(2-Ac-F- Sg): Brick-red solid, M.p. 108-110 °C

37. Ph2Sn(2-Ac-F- Sg)2: Yellowish-brown, M.p.197-199 °C

38. Ph2SnCl(2-Ac-N-St): Yellow solid, M.p. 194-196 °C

39. Ph2Sn(2-Ac-N-St)2: Peach solid, M.p.171-73 °C

40. Ph2SnCl(2-Ac-N-Sp): Sandy solid, M.p.l 10-112 °C

41. Ph2Sn(2-Ac-N-Sp)2: Brown solid, M.p.151-153 °C

42. Ph2SnCl(2-Ac-N-Sg): Light-yellow solid, M.p. 163-165 °C

43. Ph2Sn(2-Ac-N-Sg)2: White-brown solid, M.p.137-139 °C

2.1.4 Diorganotin(lV) complexes ofbibasic tridentate lV^lVO donor sulphonamide imine.

44. Me2Sn(SaH-A-St): White solid, M.p. 145-147 °C

45.Bu'2Sn (SaH-A-St): Off-white solid, M.p.140-142 °C

117 Vol. 31, Nos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

46.Ph2Sn(SaH-A-St)2: Off-white solid, M.p. 137-139 °C

2.1.5 Triorganotin(IV) complexes of bifucctional tridentate hydrazinecarbodithioic acid

47. Ph3Sn(Sal. BenzH): Light-brown solid, M.p.224 °C

48. Bu'3Sn(Sal. BenzH): Grey solid, M.p.215 °C

49. Me3Sn(Sal. BenzH): Off-white solid, M.p.239 °C

2.1.6 Organotin derivatives of benzothiazoline

50. Ph3Sn (L'H) :Light-brown solid, M.p. 197 °C

51. Bu'3Sn (L'H): Coke solid, M.p. 137 °C

52. Me3Sn (L'H): Dirty-brown solid, M.p. 195 °C

53. Ph2Sn (L'H): Reddish-brown solid, M.p.133 °C

54. Ph2Sn (ί'Η^ : Sandy-brown solid, M.p. 109 °C

55. Bu'2Sn (L'H): Grey solid, M.p.207 °C

56. Bu'2Sn (L'H)2: Light-brown solid, M.p.219 °C

57. Me2Sn (L'H): Brown solid, M.p.211 °C

58. Me2Sn (L'H^ : Coke solid, M.p.237 °C 2 59. Ph3Sn (L H): Brown solid, M.p.231 °C 2 60. Bu'3Sn (L H): Yellowish-brown solid, M.p. 199 °C 2 61. Me3Sn (L H): Light-brown solid, M.p.203 °C 2 62. Ph2Sn (L H): Sandy-brown solid, M.p.233 °C 2 63. Ph2Sn (L H)2: Brown solid, M.p.217 °C 2 64. Bu'2Sn (L H): Brown solid, M.p.227 °C 2 65. Bu'2Sn (L H)2: Light-brown solid, M.p.239 °C 2 66. Me2Sn (L H): Coke solid, M.p.207 °C 2 67. Me2Sn (L H)2: Dirty-brown solid, M.p.237 °C

2.2 Hetrobimetallic Organotin Complexes

68. [Pt(C4H| 1N3)2Sn2(Ph)4]Cl2: Red solid, M.p.195-197 °C

69. [Pt(C4H! 1N3)2Sn2(Bu')4]Cl2: Dark-brown solid, M.p.160-163 °C

70. [Pt(C4H,|N3)2Sn2(Me)4]Cl2: Yellow solid, M.p.98-100 °C

71. [Pd(C4HMN3)2Sn2(Ph)4]Cl2: Reddish-brown solid, M.p.127-129 °C

72. [Pd(C4HιiN3)2Sn2(Bu')4]Cl2: Reddish-brown solid, M.p.235-237 °C

73. [Pd(C4Hi 1N3)2Sn2(Me)4]Cl2: Reddish-brown solid, M.p.211-213 °C

2.3 Novel Chiral Organotin(IV) Complexes of Phenanthrolines/ Bipyridine

74. [Ph3Sn(l,10-Phen) (tyrosine)] : Off-white solid, M.p.123 °C

75. [Ph3Sn(4,7-Phen) (tyrosine)] : White solid, M.p. 117 °C

118 Chaudhary and Singh Main Group Metal Chemistry

76. [Ph3Sn(l,7-Phen) (tyrosine)]: White solid, M.p.128 °C

77. [Ph3Sn(l,10-Phen) (Phenylalanine.)] : Off-white solid, M.p. 103 °C

78. [Ph3Sn(4,7-Phen) (Phenylalanine.)] : Light-green solid, M.p.195-197 °C

79. [Ph3Sn(l,7-Phen) (Phenylalanine.)]: White solid, M.p.l 17 °C

80. [Ph2Sn(l,10-Phen) (tyrosine)Cl]: Cream solid, M.p.133 °C

81. [Ph2Sn(4,7-Phen) (tyrosine)Cl]: Light-green solid, M.p. 125 °C

82. [Ph2Sn(l,7-Phen) (tyrosine)Cl] : White solid, M.p. 145 °C

83. [Ph2Sn(l,10-Phen) (Phenylalanine.)Cl]: Cream solid, M.p.157 °C

84. [Ph2Sn(4,7-Phen) (Phenylalan.)Cl] : Light-green solid, M.p. 129 °C

85. [Ph2Sn(l,7-Phen) (Phenylalan.)Cl] : Off-white solid, M.p.159 °C

86. [Bu'2Sn( 1,10-Phen) (tyrosine)Cl] : Daik-cream solid, M.p. 161 °C

87. [Bu'2Sn(4,7-Phen) (tyrosine)Cl]: Greenish-white solid, M.p.127 °C

88. [Bu'2Sn(l,7-Phen) (tyrosine)Cl] : White solid, M.p. 164 °C

89. [Bu'2Sn( 1,10-Phen) (Phenylalanine.)Cl]: Cream solid, M.p.165 °C

90. [Bu'2Sn(4,7-Phen) (Phenylalanine.)Cl] : Greenish-white solid, M.p. 143 °C

91. [Bu'2Sn(l,7-Phen) (Phenylalanine.)Cl]: White solid, M.p.169 °C

92. [Me2Sn( 1,10-Phen) (tyrosinine)Cl] : Cream solid, M.p.179 °C

93. [Me2Sn(4,7-Phen) (tyrosine)Cl]: Light-green solid, M.p.134 °C

94. [Me2Sn(l,7-Phen) (tyrosine)Cl]: Off-white solid, M.p.167 °C

95. [Me2Sn( 1,10-Phen) (Phenylalanine.)Cl] : Off-white solid, M.p.183 °C

96. [Me2Sn(4,7-Phen) (Phenylalanine.)Cl]: Light-green solid, M.p. 144 °C

97. [Me2Sn(l,7-Phen) (Phenylalanine.)Cl] : White solid, M.p. 175 °C

98. [Ph3Sn(tyrosin) (bipy)] : Light-yellow solid, M.p. 128 °C

99. [Ph3Sn(Phenylala.) (bipy)] : Light-yellow solid, M.p. 139 °C

100. [Ph2Sn(tyrosin) (bipy)Cl]: Cream solid, M.p. 187 °C

101. [Ph2Sn(Phenylala.) (bipy)Cl]: Cream solid, M.p.131 °C

102. [Bu'2Sn(tyrosin) (bipy)Cl]: Off-white solid, M.p.202 °C

103. [Bu'2Sn(Phenylala.) (bipy)Cl]: Off-white solid, M.p.195-197 °C

104. [Me2Sn(tyrosin) (bipy)Cl] : Yellow solid, M.p.216 °C

105. [Me2Sn(Phenylala.) (bipy)Cl]: Yellow solid, M.p.219 °C

2.4 Unsymmetrical Macrocyclic Organotin Complexes

106. [CH3Sn(MacL)C5H5N]: Off-white solid, M.p. 232-233°C

107. [C2H5Sn(MacL)C5H5N] : Off-white solid, M.p.211-213 M.p. °C

108. [CH3Sn(MacL')C5H5N]: White solid, M.p.201-203 °C

109. [C2H5Sn(MacL')C5H5N]: White solid, M.p.215-217 °C

119 Vol. 31, Nos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

3. RESULTS AND DISCUSSION

All these complexes have been characterized on the basis of UV, IR, 'H NMR, l3C NMR and ll9Sn NMR spectroscopy 1ftQ 1 17. The most common method of pest control is by the use of chemicals, which are known as pesticides. Based on the target organisms, these pesticides are grouped into nematicides, insecticides, fungicides, weedicides and rodenticides.

4. NEMATICIDAL ACTIVITY

4.1 Experimental

The pure culture of nematode Meloidogyne incognita chitwood was maintained and multiplied on brinjal plants. For this soil was autoclaved, filled in earthen pots and seedsowing of brinjal seeds was performed. Fertilizer used was Hoagland's complete nutrient solution, 25 ml/pot once in a week. Egg masses were isolated in sterile water and the eggs were allowed to incubate in a Baermann funnel for 48-72 hours. As the juveniles hatched out of eggs, they passed through the double layers of tissue paper and collected in a tube below. The suspension was diluted with sterile water, stirred with a magnetic stirrer to obtain a homogenous suspension; 5ml of it contained the desired number of juveniles. Nematode inoculation was done when brinjal seedlings were 2 weeks old, by pipetting and pouring 5ml of juvenile suspension in three holes made around the base of seedlings, afterwards the holes were plugged with soil. The method followed for obtaining quantities of clean Meloidogyne incognita eggs was that of McClure et al. and the step by step procedure was as follows : 1. Brinjal plants infected with M. incognita were harvested from infested pots. The roots were washed thoroughly and cut into small 1-2 cm pieces. 2. The chopped pieces were placed in a beaker in 100ml of tap water, 500ml of 1% NaOCl added and the suspension was vigorously shaken for 5 minutes. 3. After a vigorous shake, the suspension was poured quickly through nested 150 and 400 mesh sieves. The eggs which were retained on the 400 mesh sieve were washed with a sufficient quantity of distilled water. 4. Eggs which passed through the 400 mesh sieve (pore size 37 μηι) were recovered by repeated sieving and rinsing.

5. Eggs were eluted from the sieves and transferred to 40 ml of water. 6. A centrifuge tube was two third filled with 20% sucrose solution and the egg-water suspension was centrifuged at 500g for 5 minutes. 7. A silver layer containing the suspended eggs at the junction of sugar solution and egg suspension was removed with the help of a pipette and quickly poured on to a 400 mesh sieve. 8. The eggs retained on the sieve were washed thoroughly three times with distilled water and collected in a beaker. 9. The eggs obtained by this method were free from debris and therefore easy to count.

120 Chaudhary and Singh Main Group Metal Chemistry

In each nematode hatching dish 200 eggs were taken and treated with the treatment. The number of juveniles were counted after 24, 48 and 72 hours. After 72 hours, sieves containing the unhatched eggs were removed from the test solution, washed thoroughly with distilled water and left in distilled water for 24 hours to record further hatching if any.

4.2. Observations

These complexes are highly active against nematode (Meloidogyne incognita) and insect (Trogoderma granarium). These studies demonstrate that the nematicidal activity increased with increasing concentration and the concentrations reached levels which are sufficient to inhibit and kill the pathogens. The tin complexes show better activity than sulphonamide imines and bimolar metal complexes were much more active than unimolar metal complexes. It was also observed that triphenyl metal complexes in 1:1 molar ratio show better activity than diphenyl metal complexes. Knowledge of the mechanism of the action of compound is important from a purely scientific point of view, which can distinguish between three different methods by which complexes can exert their action. • The effect of resonating structures such as benzene rings (in the present case) may serve as powerhouse to activate potentially reactive groupings. If toxicity is dependent on one or more chemical reactions, then any molecule which would increase the rate of chemical reactions must, perforce, enhance toxicity. • The introduction of a lipophilic substituent, either aryl or alkyl, often conferred toxicity as did the substitution of polar groups. • Complexes having amido groups or reactive halogen atoms tend to hydrolyse, to form compounds which have a modified activity spectrum. With halogen replaced by hydroxyl ion, and as a result a slight alkaline pH, the increase in activity was observed.

4.3. Mode of Action118-122

The indirect nematostatic effects of nonfumigant nematicides resulting from impairment of neuromuscular activity, interference with movement, feeding, invasion, development, reproduction, fecundity and hatching of nematodes are considered more important than their direct killing action and hence, much smaller amounts of non-fumigant than fumigant nematicides are needed in plant protection against nematodes

Table 1 Nematicidal activities of ligands and their tin complexes (25, 50 and 100 are conc. in ppm).

Complex Hatching % of Meloidogyne incognita

25 ppm 50 ppm 100 ppm

15.0 (2-Ac-F-StH) 22.5 19.0

121 Vol. 31, Nos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

Me2SnCI (2-Ac-F-St) 19.3 15.5 nil

Me2Sn(2-Ac-F-St)2 15.8 11.8 nil

Ph2SnCl(2-Ac-F-St) 17.5 14.8 nil

Ph2Sn(2-Ac-F-St)2 13.3 9.9 nil

Ph3Sn(2-Ac-F-St) 16.4 13.7 nil

(2-Ac-F-SpH) 24.0 20.7 16.3

Me2SnCl (2-Ac-F-Sp) 20.4 17.0 nil

Me2Sn(2-Ac-F-Sp)2 17.6 13.4 nil

Ph2SnCl(2-Ac-F-Sp) 18.8 16.5 nil

Ph2Sn(2-Ac-F-Sp)2 14.1 11.3 nil

Ph3Sn(2-Ac-F-Sp) 17.8 14.8 nil

(2-Ac-F-SgH) 25.8 21.4 15.9

Me2SnCl (2-Ac-F-Sg) 21.8 18.7 nil

Me2Sn(2-Ac-F-Sg)2 17.5 15.0 nil

Ph2SnCl(2-Ac-F-Sg) 19.6 17.3 nil

Ph2Sn(2-Ac-F-Sg)2 15.1 12.5 nil

Ph3Sn(2-Ac-F-Sg) 18.7 15.1 nil

(2-Ac-N-StH) 21.9 17.3 13.1

Me2SnCl(2-Ac-N-St) 18.0 14.0 nil

Me2Sn(2-Ac-N-St)2 15.0 11.0 nil

Ph2SnCl(2-Ac-N-St) 16.0 13.0 nil

Ph2Sn(2-Ac-N-St)2 12.0 9.0 nil

Ph3Sn(2-Ac-N-St) 14.0 12.0 nil

(2-Ac-N-SpH) 23.6 19.0 ,4.2

122 Chaudhary and Singh Main Group Metal Chemistry

Me2SnCl(2-Ac-N-Sp) 20.0 15.4 nil

Me2Sn(2-Ac-N-Sp)2 16.9 13.0 nil

Ph2SnCl(2-Ac-N-Sp) 18.0 15.5 nil

Ph2Sn(2-Ac-N-Sp)2 13.5 10.4 nil

Ph3 Sn(2-Ac-N-Sp) 15.8 11.0 nil

(2-Ac-N-SgH) 24.1 19.8 15.0

Me2SnCl(2-Ac-N-Sg) 20.2 16.4 nil

Me2 Sn(2-Ac-N-Sg)2 17.7 13.1 nil

Ph2SnCl(2-Ac-N-Sg) 18.9 15.7 nil

Ph2Sn(2-Ac-N-Sg)2 14.3 10.2 nil

Ph3 Sn(2-Ac-N-Sg) 16.0 11.6 nil

(SgH-A-StH) 18.2 14.6 11.5

Me2Sn(sa-A-St) 13.6 11.1 nil

Ph2Sn(sa-A-St) 12.0 9.6 nil

Ph3Sn(Sa-A-StH) 11.2 9.1 nil

5. INSECTICIDAL ACTIVITY

5.1 Significance and Historical Notes

The oldest insecticides used by humans were of plant origin. These were prepared from the roots, stems, leaves, seeds, flowers and oils of various plants. These botanical pesticides were followed by the development of inorganic synthetic insecticides like Paris green, lead arsenate and calcium arsenate. In 1867,

Paris green, a crystal compound of acetate and arsenite of copper, having the approximate composition Cu4

(CH3C02)2 (AS02)2 was successfully used for the control of Colorado potato beetle in USA. Another arsenic compound, lead arsenate (PbHAs04) was first used against Gypsy moth in USA in 1892. Inorganic compounds containing mercury, tin or copper were also used as stomach poisons during this period. In the early 1900s, sodium fluoride and cryolite replaced some arsenicals because of lower phytotoxicity.

123 Vol. 31, Nos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

With the development of these insecticides, the focus of research in entomology slowly shifted from ecological and cultural control practices to chemical control during the period 1920 - 1945. The first synthetic organic compounds to be used as insecticides were alkyl thiocyanates prepared by reaction of alkyl halides with sodium thiocyanate during the 1930s. Another compound, Lethane, consisting of ether linkages in alkyl chains, was prepared in 1936. The development of these compounds was perhaps prematurely arrested by the dramatic success of DDT [2,2-bis-(p-chlorophenyl)-1,1,1 -trichloroethane]. The impact of DDT on pest control is perhaps unmatched by any other synthetic substance and Paul Muller was awarded the Nobel prize in 1948 for discovering the insecticidal properties of DDT. Nearly 1.5 billion kg of DDT was used during the three decades following its introduction in agriculture during the 1940s. By 1961, there were over 1200 brands of DDT registered for use on 334 agricultural commodities against 240 species of insect pests in USA. The period since the 1940s has rightly been called the 'age of pesticides' and can be divided into three distinct phases the era of optimism, 1946 - 1962; the era of doubt, 1962 - 1976; and the era of JPM, 1976 - onwards.123 Many insects are responsible for incalculable harm to human beings in several ways and have been directly or indirectly responsible for more loss of life and destruction of food products than that caused by wars, floods and famines. Every year they have been destroying our agricultural products as well as stored commodities in different ways, the cost of which runs into millions of rupees. Work has already been done on a large number of harmful insects in respect to their bionomial characters and physiological activities. Nevertheless, continued research work is desirable to take effective defence measure against these pests, which are enemies of social and economic progress, so as to substantially reduce the enormous wastage and also to facilitate national development.124 Based on their activities the insects may be placed in three categories i.e. beneficial, harmful and neutral insects, which neither harm nor benefit man. Since the insects are better adapted to occupy the earth, both by means and mechanism of survival, their harmful impacts on human health and economy are also diverse and intense. They consume, destroy and damage all kinds of growing crops and their valuable vegetation, injure man and his domestic animals and disseminate, as vector, many deadly diseases such as filariasis, malaria, dengue, yellow fever, encephalitis, sleeping sickness and leishmaniasis.125 Many insects cause unaccountable damage to stored products and other commodities such as food, grain, paper, books, furniture, timber, and clothing. The greatest importance of insects lies in their being pests of crops and animals. A pest is an animal whose population buildup increases above certain level of economic injury and its existence conflicts with man's welfare, convenience and profit.125 Besides attacking the food grains, the presence of insect pests not only results in accumulation of anti- nutrients like polyphenols, phytic acid and uric acid in cereal but causes significant changes in lipid, carbohydrate134, minerals and protein, nitrogen, starch digestibility. This nutritional imbalance also leads to poor utilization and availability of cereal protein in animals.125 Trogoderma granarium (Everts), commonly known as khapra beetle, belonging to the coleoptera and dermestidae family, is an important pest of both material of plants and animal origin. It is said to be of Indian origin and has spread to the whole world due to ship transportation. It is a major pest of stored wheat in hot and dry parts of the world. The damage is sometimes so serious that the whole grain is reduced to husk and

124 Chaudhary and Singh Main Group Metal Chemistry

only seed coats with empty cavities are left behind. Besides wheat it generally infects cereals, pulses, stored malt, rice and coriander seeds.125 Man has from time to time employed various strategies which include natural, physical, mechanical, biological, chemical, control, parasites, predators, microbial, viral insecticides, chemosterilants, resistant variety, breeds of animals, improved village practices, crop rotations and electromagnetic energy in pest management program. The literature on the insecticidal activity of organotin compounds through 1964 has been reviewed very completely by B. A. Richandson126. Therefore only the main lines will be discussed here and a few recent publications mentioned. The first mention of insecticidal properties in organotin compounds was made in a series of patents published around 1929. In addition to compounds of Group V elements, organotin compounds in general were claimed as mothproofing agents (139). Twenty years later only trialkyltin chlorides were claimed in a patent127dealing with the control of insects other than moths. Hueck and Luijtenl28in 1958, found mothproofing activity only in some compounds of the type R3SnX. Systematic investigations on the insecticidal activity of organotin compounds started with the work of Blum et al. in 1960. Kahana129 had already shown that triethyltin hydroxide and some of its salts were hightly toxic when applied topically to house flies (Musca domestics). The LD50 of the compounds was somewhat higher for DDT-resistant flies than for susceptible flies (e.g. of the hydroxide, 0.40 μg as compared with 0.31

Mg per fly) for compounds of the type R4Sn and R2 and R2SnX2. Neither the nature of the group X nor the length of the alkyl chains (at least up to butyl) had much influence on the insecticidal activity. A similar result was obtained by Klimmer et α/.130 who tested a series of organotin compounds in aqueous solution against mosquito larvae (Culex pipiens berbericus). They extended the series of trialkyl compounds somewhat further, however, and found a sudden fall in activity after hexyl. The concentration of trialkyltin compounds killing half of the larvae(LC50) from methyl through hexyl was 0.4-0.5 mg/1. This is still ten times the LC50 of DDT, lindane, and malathion in the same test. In the above investigations, triphenyltin compounds had the same activity as the lower trialkyltin compounds. Kochkin et α/.131 likewise investigated a series of organotin compounds, but extended the number of insects to include flies, bed bugs, cockroaches, mosquitos and fleas. The flies were treated topically; the LDso's found correspond with those observed by Kolditz 132. The Russian authors moreover found trialkyltin compounds active as contact insecticides against all species. Conflicting results were obtained with triphenltin compounds: Leusink 133, when testing a series of ten triphenyltin salts as contact insecticides against Sitophilus oryzae adults, found none active. One wonders, however, whether in the latter investigation the experimental set-up was favourable. Where Kochkin et al. used glass plates, Gardiner and Poller used paper discs, and it is known that organotin compounds are fixed by cellulose134. Marks 135 who investigated the activity of triphenlytin organphoshates as contact insecticides against the adult Azukibean weevil (Cellosobruchus chinensis) again used glass (Petri dishes). A strong influence of the nature of the acid radical was noted in this case, and Kubo could demonstrate a correlation between the activity and the solubilitA differency of thee compound in the mods ien organiof actioc solventsn betwee. n trialkyl-and triphenyltin compounds is suggested by the

125 Vol. 31, Nos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

results of mothproofing tests by Kubo et al.135. In these tests, tested samples of wool were exposed to attack by larvae of the common clothes moth (Tineola bisselliella). The authors found no attack and 100% kill with 1% of tributyltin oxide in the wool. With triphenyltin salts in the same concentration some wool was always eaten and the kill percentage never attained 100%. The authors concluded that tributyltin oxide acts as a contact insecticide but the triphenyltin salts as stomach poisons. Their observation that the nature of the acid radical in the triphenyltin salts has a distinct influence on the insecticidal activity agrees with Marks136 A limited series of organotin compounds was tested by Kubo et al,135 against larvae of the bollworm

{Heliothis zed) and the tobacco bud worm (Heliothis virescens). On topical application the following LD50's were found: trimethyltin hydroxide and acetate about 0.2 μg/larva, tribtyltin oxide and diethloctyltin acetate about 5μg/larva and trihenyltin hydroxide and acetate more than 10 μg/larva. A small but consistent difference in sensitivity was noted between insecticide resistant and susceptible strains. A few investigators examined only one compound, in most cases the commercially available tributyltin oxide. Richardson134 tested tributyltin oxide in powdered biscuits against the larvae of the drug-store beetle (Stegobium paniceum) a close relative of the common furniture beetle (Anobium punctatum). One tenth of a percent was sufficient in the long run to kill all larvae.

A compound of the type R2SnX2, the commercially available dibutyltin dilaurate (used both as a stabilizer in PVC and as an anthelmintic in poultry), has repeatedly been tested in vivo against endo-parasitic insect larvae in cattle. The larvae of the so-called heel files (Hypoderma lineatum and H. bovis), known as cattle grubs, live under the skin of cattle. After initial success, however , only negative results have been obtained137·138 . An organotin compound of quite another type, viz. hexamethylditin, has recently been introduced as an agricultural insecticide under the trade-name Pennsalt TD-5032139. It has been used against several species of noctuidae139 and it has been shown to be systemic in cotton140. The formulated product loses its activity upon standing, but it can be stabilized141. Organotin compounds, in addition to a toxic effect, can exert an "antifeeding" effect on insects. The antifeeding effect, which is probably based on taste, occurs at very low, sublethal concentrations. It has so far only been described for triphenyltin compounds. After its discovery in field tests, in which triphenyltin hydroxide and acetate had been used as agricultural fungicides, laboratory experiments have confirmed its existence. Pennsalt et α/.142 showed that leaves of sugar beet, sprayed with suspensions of triphenyltin acetate of increasing concentrations, were eaten to a decreasing extent by larvae of two kinds of moths. Prodenia litura and Agortis ypsilon. Protection of the leaves was about 90% at the 0.035% concentration. Further experiments against P. litura with triphenyltin hydroxide and acetate showed the latter to be superior to the former. The results offer the capability of quantitative treatment. The superiority of the acetate over the hydroxide was also borne out in experiments with larvae of the potato tuber moth (Gnorimoschema operculella) and the striped maize borer (Chilo agamemnon). No complete protection against these insects was obtained, however, even at the highest concentration employed (0.05%)143 In tests with larvae of the Colorado potato beetle (Leptinotarsa decemlineate), Duphar144 compared the antifeeding activity of a series of triphenyltin compounds. From experiments acetate emerged as the most active. The antifeeding effect of triphenyltins on the housefly larva was again investigated by Pennsalt et alul. Triphenlytin hydroxide and acetate were added to moistened wheat bran in concentrations of 10-40 mg/kg. At these concentrations,

126 Chaudhary and Singh Main Group Metal Chemistry

parallel to a moderate antifeeding effect, a toxic effect was observe for both compounds145. Also hexamethylditin has been found to posses antifeeding properties146. Another effect exerted by organotin compounds at low concentrations and likewise only demonstrated for triphenyltin compounds, is their ability to, interfere with insect reproduction. The first report on insect chemosterilant activity of triphenlyltins came from Plapp 147: of the more active compounds in his tests, the fluoride, hydroxide and sulfide caused sterility in house flies well below the lethal concentration. Other insects whose reproduction could be influenced were the german cockroach (Blatella germanica) and the confused flour beetle (Tribolium confusum). Kenaga et. α/.148 included the Colorado potato beetle in tests with triphenlytin compounds. Triphenyltin acetate and chloride according to Kissam and Hays were already quite toxic concentrations required for sterilizing house flies149. The mode of action of organotin compounds on insects is not known with certainty. Investigations by Stoner150 on the inhibition of adenosine triphosphatases in the house fly have revealed a correlation between potency for in vitro ATPase inhibition and toxicity of triorganotins. The authors suggest that the insectical activity of triorganotins may result from interference with ATPase activity or related processes which confer resistance to organotin insecticides and act as intensifier of parathion reistance151. It has been shown that this gene acts by decreasing the rate of absorption150.

5.2. Recent Developments

Insecticidal screening data (Tables 2-5) of a series of organotin compounds reveal that the complex ' ' ' ' I

Ph3Sn(Sa-A-StH) is more toxic than other tin complexes. Tin complexes are more active than the parent ?alicylalanilide sulphathiazole ligand. Dimethyltin complexes are less active than their triphenyltin complexes112·116. · ' ' , ••'..,'• Insecticides act on target organisms in different ways depending on their physical and chemical makeup. Some insecticides are physical poisons causing asphyxiation, some are protoplasmic poisons, a, few are respiratory poisons, but the majority of them are nerve poisons. The action of insecticides upsets the normal behaviour and actions of the target organisms and the surest and quickest way to achieve this is to poison the nervous system. J

Table 2 Ovicidal action. Compound . ' Dose Average no. of Average ho. of % eggs , % eggs % Corrected level eggs hatched eggs unhatched hatching unhatched molality , (SaH-ArStH) 100 14 6 70 , 30 26.31 (SaH-A-StH) 200 12 8 60 40 36.84 ,

Me2Sn(Sa-A-St) 100 1,1 9 ' 55 . ' 45 42.10

Me2Sn(Sa-A-St) 200 ' • 7. 13 35 65 63,15

Ph2Sn(Sa-A,St) 100 ' 10 JO '50 50 47.36

Ph2Sn(Sa-A-St) 200 .5. · 15 25 .75 73.68

127 Vol. 31, Νos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

Ph3Sn(Sa-A-StH) 100 8 12 40 60 57.89 Ph3Sn(Sa-A-StH) 200 4 16 20 80 78.94

Table 3 Larvicidal action.

Compound Dose Average no. of Average no. % pupal % larval % corrected level pupae formed of dead larvae formation mortality mortality (SaH-A-StH) 100 15 5 75 25 21.05 (SaH-A-StH) 200 12 8 60 40 36.84

Me2Sn(Sa-A-St) 100 11 9 55 45 42.10 Me2Sn(Sa-A-St) 200 8 12 40 60 57.89 Ph2Sn(Sa-A-St) 100 9 11 45 55 52.63 Ph2Sn(Sa-A-St) 200 5 15 25 75 73.68 Ph3Sn(Sa-A-StH) 100 8 12 40 60 57.89

Ph3Sn(Sa-A-StH) 200 5 15 25 75 73.68

Table 4 Pupicidal action.

Compound Dose No. of adults Average no. of % emerged % pupal % corrected level emerged pupal mortality adult mortality mortality (SaH-A-StH) 100 14 6 70 30 26.31 (SaH-A-StH) 200 13 7 65 35 31.57

Me2Sn(Sa-A-St) 100 12 8 60 40 36.84

Me2Sn(Sa-A-St) 200 8 12 40 60 57.89

Ph2Sn(Sa-A-St) 100 10 10 50 50 47.36

Ph2Sn(Sa-A-St) 200 6 14 30 70 68.42

Ph3Sn(Sa-A-StH) 100 9 11 45 55 52.63

Ph3Sn(Sa-A-StH) 200 5 15 25 75 73.68

Table 5 Pupicidal action.

Compound Dose No. of adults Average mortality % Adult % Corrected level in each vial after 48 hours mortality mortality (SaH-A-StH) 100 20 5 25 21.05 (SaH-A-StH) 200 20 7 35 31.57

Me2Sn(Sa-A-St) 100 20 9 45 42.10

Me2Sn(Sa-A-St) 200 20 13 65 63.15

Ph2Sn(Sa-A-St) 100 20 11 55 52.63

128 Chaudhary and Singh Main Group Metal Chemistry

Ph2Sn(Sa-A-St) 200 20 14 70 68.42

Ph3Sn(Sa-A-StH) 100 20 12 60 57.89

Ph3Sn(Sa-A-StH) 200 20 14 70 68.42

6. ANTIFERTILITY ACTIVITY

6.1. Background Informations

With the ever-growing world population, contraception is an important health issue for the 21 st century. Fertility is an issue of global and national public issues concerning the rapid growth of the country. For the total world population of the preceding century, the rate of increase of the population was about 10 million per year. Now it is increasing at a much faster rate of 100 million per year. If the rate of increase remains continuous at the same pace, it is expected to reach 7 billion by the end of the present century. The rapid increase of population has an adverse effect on the international economy and as the increase is only limited to the developing countries, the problem becomes acute on the fruits of improvement in the different sectors, which are being eroded by the growing population. Moreover, increasing number of births has a deleterious effect on the health of mother and child and hinders social and economic progress. The regulation of human fertility has global consequences in terms of resources depletion, population and poverty. Now, it has become one of the priorities of the National Family Programs and therefore, there is an urgent need to improve the access and the quality of contraceptive service in the country. Contraceptive methods are, by definition, preventive methods to help women to avoid unwanted pregnancies. This includes all temporary and permanent measures to prevent pregnancy resulting from coitus. The last few years have witnessed a contraceptive revolution, i. e., man trying to interface with the ovulation cycle. It is now generally recognized that contraception is safe, effective, acceptable, inexpensive and reversible and simple to administer, is long lasting enough to avoid frequent administration and requiring little or no medical intervention. The international efforts to develop improved means of fertility control are based on the premise that the nature of available fertility control technology is highly important and determinant for the success of planning programs. The primary requisite of an antifertility agent for humans is that it should be non-toxic, non-teratogenic and should not interfere with the normal metabolic and behavioral process. Further, the method should be reversible. Therefore, exhaustive and prolonged studies on the safety and efficacy of contraceptive agents including their effect on progeny in laboratory animals should precede studies on human volunteers. Each contraceptive method has its unique advantage and disadvantage. The success of any contraceptive method depends not only on its effectiveness in preventing pregnancy but on the rate of continuation of proper use.

Chemical Contraception

Chemical control of fertility in the male has received attention since quite some time and a large number of steroidal and non-steroidal substances have been tested for their antispermatogenic and antiandrogenic

129 Vol. 31, Nos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

effects, but in general attempts made in this direction have failed to pass the initial laboratory and clinical trials. Practically, all major research on new oral contraceptives is based on synthetic compounds; particularly, steroidal derivatives have considerable efforts so far being put forward to suppress spermatogenesis by a variety of steroidal and non-steroidal agents. A large number of antispermatogenesis compounds have been reviewed; to name a few: dichloroacetyl diamines, derivatives of sulphonic acids, dinitropyrrol, nitrofuran, methylhydrazine and calcium chloride effectively inhibit spermatogenesis in a number of laboratory species. However, none of these were clinically promising since most of them had mutagenic, carcinogenic or most toxic side effects at the effective dose level. Also, the produced testicular changes in many instances were irreversible.

DL-204[2-(3-ethoxyphenyl), 5,6-diahydro(5,l-a)-iso-quinoline], a non-steroidal compound, showed antiandrogenic activities by reducing accessory sex organ weight and also exhibited antispermatogenic activities. It is reported that DL-204 might be acting on testes and accessory reproductive organs by blocking androgen biosynthesis and/or antagonizing the action of androgen152.

6.2. Recent Developments

An ideal chemical contraceptive for males would be one which effectively arrests the production of sperms (spermatogenesis) or inhibits sperm fertilizing capacity without altering libido, accessory sex organs and pituitary function and one which is easily administrable. The facts reported above are true in the case of human beings. However, similar treatment is possible in the case of animals. Since the present studies are related to the development of new pesticides, the experiments have been done on rats and not on human beings. The preliminary studies on rats are in the positive direction and need further deep studies on the subject. Here studies in vivo for one ligand and its silicon, tin and manganese complexes have been attempted and the obtained results are described in the following pages:

6.2.1. Diorganotin(IV) complexes ofbibasic tridentate Γ^^ΓΟ donor sulphonamide imine. Male rats exposed to ligands and their tin complexes showed altered reproductive activity.

• Body and organ weight There were no significant differences in the body weight at the end of the experimental period among the treated groups as compared with the controls (Table 12). However, the weights of testes, epididymis, seminal vesicle and ventral prostate were decreased significantly in ligand (P < 0.01) and its various complexes (P < 0.01 to 0.001) as shown in Table 6.

• Sperm dynamics and fertility The sperm motility in cauda epididymis was decreased significantly in animals treated with ligand (P < 0.01) and its complexes (P < 0.001), as shown in Table 7. Also, a significant decrease in sperm density in testes and cauda epididymis (P < 0.01 to 0.001) was observed in rats treated with ligand and its various complexes.

130 Chaudhary and Singh Main Group Metal Chemistry

• Biochemical changes Marked reductions (P < 0.01 to 0.001) in sialic acid and protein contents of testes, epididymis, ventral prostate, and seminal vesicle were observed in the animals treated with ligand and its complexes when compared with controls in Table 8. However, a sharp increase in testicular cholesterol, acid and alkaline phosphatase contents were observed in various treated groups. Seminal vesicular fructose contents decreased significantly as shown in Table 14.

Discussion In the present study, ligand and its complexes were administered to rats at the dose levels 9-50 mg/kg/day for 60 days, which brought about marked alterations in the weights of testes, epididymis, seminal vesicle and ventral prostate. Significant decline in the testes weight may be due to the decrease in number of spermatogenic elements and spermatozoa.153 Reduction in weight of sex accessory organs directly supports the reduced availability of androgens.154'155 Suppression of gonadotropins might have caused decrease in sperm density in testes.156 Low caudal epididymal sperm density may be due to alterations in androgen metabolism157"159and 65% to 100% negative fertility may be attributed to lack of forward progression and reduction in density of spermatozoa and altered biochemical millieu of cauda epididymis.160"161 Decline in total protein concentration in testes and other accessory reproductive organs indicated suppressed androgen activity.162'163 Further, reduced contents of sialic acid in various reproductive organs reported herein suggest adverse effects on the metamorphosis and maturational stages of spermatid164 The rise in the testicular cholesterol contents due to various compounds treatment suggests suppressed androgen biosynthesis.165 An increase in testicular acid and alkaline phosphatase activities indicate metabolic disturbance and impairment of the functional integrity of the testes.166

Table 6 Effects of ligand and its tin complexes on the body and reproductive organ weights of male rats. Compound Body weight (g) Testes Epididymis Seminal Ventral prostate vesicle Initial Final <- mg /100 g body weight -» A Control 235.0 ± 245.0 ± 1350.0 ± 460.0 ± 505.0 ± 480.0 ± 15.0 17.0 30.8 13.0 32.0 21.0 Β (SaH-A-StH) 220.0 ± 230.0 ± 1210.0 ± 410.0 ± 422.0 ± 400.0 ± 17.0 15.0 15.0" 10.0a 15.0a 20.0"

C Me2Sn(Sa-A-St) 227.0 ± 238.0 ± 1040.0 ± 280.0 + 308.0 ± 310.0 ± 16.0 15.0 19.0b 15.0b 16.0b 16.0b

D Ph2Sn(Sa-A-St) 232.0 ± 239.0 + 900.0 + 250.0 + 300.0 ± 290.0 + 14.0 17.0 30.0b 20.0b 17.0b 15.0b

Ε Ph3Sn(Sa-A- 228.0 ± 235.0 ± 870.0 ± 210.0 285.0 ± 270.0 + b StH) 15.0 16.0 18.0b + 21.0b 18.0" 17.0 Values are mean + SEM six determinations a = Ρ < 0.01 ;b = P< 0.001

131 Vol. 31, Nos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

Group A compared with Group B. Group C compared with Group B. Groups D, E, F, G, Η and I compared with Group B.

Table 7 Altered sperm dynamics and fertility after treatment with ligand and its tin complexes.

Treatment Sperm motility Sperm density (million/ml)

cauda epididymis Testes Epididymis A Control 70.0 + 6.10 1.90 + 0.20 51.0 ± 1.85 98.1 +ve Β (SaH-A-StH) 60.0 + 3.0" 1.08 + 0.10a 42.0+ 1.70" 65% -ve

b b b C Me2Sn(Sa-A-St) 38.0 + 6.0 0.61 +0.18 25.0+ 1.80 95% -ve

b b b D Ph2Sn(Sa-A-St) 35.0 + 7.0 0.51 +0.20 22.0+ 1.30 98% -ve

b b Ε Ph3Sn(Sa-A-StH) 30.0 + 7.1" 0.35 +0.10 20.5 + 1.60 100%-ve Values are mean + SEM six determinations a = Ρ < 0.01 ; b = Ρ < 0.001 Group A compared with Group B. Group C compared with Group B. Groups D, E, F, G, Η and I compared with Group B.

6.2.2. Triorganotin(IV) Complexes of Bifunctional Tridentate Hydrazinecarbodithioic acid

No significant changes were noticed in the body weight after the treatment of ligand (Sal.Benz.H2) and its complexes at 2 mg, 4 mg and 7 mg dose levels/ per day for 60 days,similarly no significant changes were observed at 2 mg, and 4 mg dose level of (CH3)3Sn(Sal.Benz.H)and (C6 H5)3Sn(Sal.Benz.H) in the body weight of rats, when compared with their initial body weight. Oral administration of ligand and complexes caused significant reduction (P < 0.01) in the weight of testes and accessory sex organs, whereas no changes were observed in the weight of kidney and adrenal glands. Sperm motility of cauda epididymides and sperm density of the testes and cauda epididymides was decreased significantly (P < 0.001) in rats treated with ligand and its complexes at all the dose levels (Tables 9-11). 40 to 65 percent negative fertility was observed at different dose levels of ligand and its various complexes.

Total erythrocyte count (TEC), total leukocyte count (TLC), hemoglobin concentration, hematocrit and blood urea values were in the normal range after ligand treatment, whereas tin complexes (CH3)3Sn(Sal.

Benz.H)and (C6H5)5Sn(Sal.Benz.H) showed increased values in total leukocyte (TLC) and blood urea. No change was observed in total erythrocyte count (TEC), hemoglobin concentration and hematocrit at all the dose levels (Tables 12-14). Total protein contents and sialic acid concentration of testes and accessory sex organs were significantly reduced after administrtion of the ligand and its complexes. Administration- reduced level of testicular glycogen and cholesterol were noticed following the administration of the ligand and its tin complexes at all dose levels (Tables 15-17). Histopathology of testes treated with different doses exhibited drastic changes. Most of the tubules showed more or less spermatogenic arrest. However, the damage was not uniform. Residual sperms and the cell debris were present in the lumen of some tubules.

132 Chaudhary and Singh Main Group Metal Chemistry

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133 Vol. 31, Nos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

Interstitial stroma had slight atrophy and nacrotic nuclei. The epididymis showed normal epithelium. The intertubular stroma appeared to be degenerated

Table 9

Sperm Dynamics and Fertility after treatment with Salicylanilide-S-Benzylditithiocarbzate (Sal. BenzH2).

Sperm motility (%) Sperm density (million/ml) Fertility Rate Treatment (Cauda Cauda Testes (%) epididymides) epididymides Control 68.65 4.13 35.70 98 (+ve) Group I ±2.2 ±0.4 ±2.90 2mg/day for 60 days 50.13* 2.89* 23.69* 40 (-ve) Group II ±3.6 ± 0.09 ±2.4 4mg/day for 60 days 48.65* 2.18* 17.21* 50 (-ve) Group III ±5.2 ±0.3 ±3.3 7mg/day for 60 days 39.45** 1.91** 14.05** 65 (-ve) Group IV ± 1.9 ±0.01 ±0.9 (Mean ± SEM of 6 animals) ns = Non significant * = P<0.01 - significant ** = Ρ < 0.001 - Highly significant

Table 10

Sperm Dynamics and Fertility after treatment with (CH3)3 Sn(Sal. Benz. Η).

Sperm motility (%) Sperm density (million/ml) Fertility Rate Treatment (Cauda Cauda Testes (%) epididymides) epididymides Control 70.11 4.1 31.91 100 (+ve) Group I ±0.53 ±0.06 ±3.3 2mg/day for 60 days 39.41** 1.59** 14.59** 80 (-ve) Group II ±3.3 ±0.2 ±0.9 4mg/day for 60 days 28.01** 0.89** 7.46** 90 (-ve) Group III ±3.01 ±0.02 ±3.1 (Mean ± SEM of 6 animals) ns = Non significant * = P<0.01 - significant ** = Ρ < 0.001 - Highly significant

134 Chaudhary and Singh Main Group Metal Chemistry

Table 11

Sperm Dynamics and Fertility after treatment with (C6H5)3Sn(Sal.Benz.H).

Sperm motility (%) Sperm density (million/ml) Fertility Rate Treatment (Cauda Cauda Testes (%) epididymides) epididymides Control 70.16 4.95 39.32 100 (+ve) Group I ±0.22 ±0.01 ±0.59 2mg/day for 60 days 37.91** 2.91** 18.97** 75 (-ve) Group II ± 1.3 ±0.2 ± 1.07 4mg/day for 60 days 19.68** 0.99** 9.75** 95 (-ve) Group III ±4.9 ±0.06 ± 1.1 (Mean ± SEM of 6 animals) ns = Non significant • = P< 0.01 - significant ** = Ρ < 0.001 - Highly significant

Discussion In the present study the results indicated that the weights of the body and vital organs were not affected after the treatment, suggesting that the complexes have no side effect or toxicological effect and maintained normal physiology of the animals throughout the experiment. (i) Chinoy et α/167 reported that the structural and functional integrity of the reproductive organs depends on the circulating level of the androgen and any small change in the androgen level results in the reduction in the weights of the reproductive organs. In the present studies decline in the circulating levels of testosterone was

observed in (CH3)3Sn(Sal.Benz.H) and (C6H5)3Sn(Sal.Benz. H) treated animals, leading to a decrease in the organ weights and androgen dependent parameters. • The reduction in the weight of the testes after the treatment in the present study related to the loss of spermatozoa and spermatids, which make up a substantial proportion of testicular volume, by the same token, as a consequence of disruption of spermatogenesis.168"170 • The suppressed epididymal activity as evidenced by the loss of weight and histological alterations might be due to anti-gonadotrapic activity of the so-termed anti-androgenic/estrogenic substances, which lower the ABP production by the Stertoli cell and androgen synthesis by the Leydig cells, thereby resulting in reduced levels of androgen available to the epididymis for functional maintenance. The requirement of relatively higher androgen threshold in the epididymis has already been established by Gupta et a/.171 • Reduction in the weights of seminal vesicles, ventral prostate and vas deferens also reflects an interference with androgen output. Bhigwade et al.m have already correlated the reduction in the weights of sex-accessories, particularly of the prostate, following treatment with cyproteron acetate. Antiandrogens are known to depress the uptake of testosterone in the prostate and reduce binding of androgen to the hormonal receptors by a process of competitive inhibition, as reported by Sharma et α/.173

135 Vol. 31, Νos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

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• The sperm density and sperm motility have a direct relationship to the fertility. 174In the present study

sperm motility and density of testis and cauda epididymis after (CH3)3Sn(Sal.Benz.H) and 175 (C6H5)3Sn(Sal.Benz.H) treatments were significantly decreased. Rao has reported declined sperm motility, resulting in decreased fertility. • Immotile or sluggishly motile spermatozoa can not penetrate the cervical mucus and thus fail to fertilize the ova.176 During the present course of the study, a 90% negative fertility rate was observed after

(CH3)3Sn(Sal.Benz.H) treatment, while it was 72% negative in the(C6H5)3Sn(Sal.Benz H) treated animals. It appears worthwhile to conclude that reduction in the sperm counts and motility, recorded in treated animals, substantiates the antifertility activity. Further, alteration in the various androgen-dependent biochemical parameters, that in turn altered the internal milieu of the epididymis177, may also be responsible for the negative fertility test. Withdrawal for 30 days in the groups treated with

(CH3)3Sn(Sal.Benz.H) and (C6H5)3Sn(Sal.Benz.H) showed significant recovery in the fertility rate, indicating that the effects brought about by the synthetic compounds were reversible. • Protein is involved in the alteration of almost every physiological system, and the total protein runs parallel to the growth and is sensitive to estrogen and androgen, respectively, as reported by Davis et al,177 Jones et α/.178 have reported that protein level is directly correlated with the secretory activity of the epididymis, which in turn depends on the androgen levels. • In the present investigations the reduction in the protein concentration by the treatment may be attributed to the reduction in secretory activity because of the androgen deprivation effect. Kamal et al,179 and Mali et al.180 also reported similar results for male albino rats. • Nag et al.m have reported that an optimal level of sialic acid in reproductive organs is essential for functional integrity of spermatozoa. Our observations are in consonance with those of Gupta et α/.182, who have reported a decrease in sialic acid concentration of testis, cauda epididymis, seminal vesicle and ventral prostate to albino rats. Bhargava183 reported a decrease in the testicular sialic acid concentration due to the antispermatogenic activity. • Mammalian cells require cholesterol, which also plays an important role in acting as precursor molecule in the synthesis of steroid hormone.184 The requirement of cholesterol for normal activity of testicular glands has been well established by Biswas.185Androgens are synthesized from cholesterol, but increased concentration may result in the reduction of fertility.186 > After treatment with the effective doses of both compounds, there was a significant increase in the testicular and adrenal cholesterol concentration, which is in consonance with the results of Kamal et α/.179, suggesting that the increased testicular cholesterol concentration may be correlated with' its non- utilization by the system, leading to a fall in circulatory androgen in rats due to the antiandrogenic activity., • Baijal et α/.187 proposed that glycogen might represent a source of nourishment for the spermatozoa during their development and maturation. The glycogen level declined in testes and liver of the rats' 235 treatment with (CH3)3Sn(Sal.Benz.H). Kamal et al. have reported decreased concentration of glycogen in the rats due to its androgen dependence, leading to various disorders in testes.

In contrast, treatment with (C6H5)3Sn(Sal.Benz.H) caused a non-significant increase in the concentration

142 Chaudhary and Singh Main Group Metal Chemistry

of glycogen of both the liver and testes. The same case has also been reported by others.188 Increased carbohydrate utilization has been considered due to androgenic stimulation, suggesting a direct correlation between testosterone secretion rate and glucose uptake by the isolated and perfused rabbit testis by Ewing et α/.188

• After treatment with effective doses of (CH3)3Sn(Sal.Benz.H) and (C6H5)3 Sn(Sal. Benz.H), there was a decrease in the testicular and cauda epididymal_ascorbic acid concentration, which is in consonance with the findings of Chatterjee189, who reported hypofiinctioning of testis and the degeneration of the germinal epithelium due to vitamin C deficiency. <> • Decline in acid phosphate level might be due to antiandrogenic effect or might be due to suppressed secretory function of the prostate. The acid phosphate values during the present course of the study concurs with the findings of Fang et al.m

Administration of the test substances resulted in a significant reduction in the alkaline phosphate content of the ventral prostate. It is evident that this decrease was a likely consequence of spermatogenic arrest as a result of suppression of androgen. This observation concurs with the findings of others also179'186 190, who reported a general decline in the alkaline phosphate content of the various reproductive and accessory organs of the male rats after androgen-estrogen therapy.

6.2.3. Organotin derivatives of benzothiazoline The results (Table 18) with benzothiozoline derivatives may also be correlated with the well-known fact that sulphur-containing compounds produce infertility in male rats96 Thus it can be postulated that chelation through sulphur atoms induces the sterilizing activity in the biological systems.

Table 18 Effects of various compounds of sperm dynamics and fertility of male rats

Compound Sperm motility Sperm density Fertility test (%) (Cauda (20 mg dose levels/ Testes Cauda epididymis) per day) epididymis

Vehicle alone (olive oil) 78.5 ±4.8 4.3 ± 0.42 61.1 ±4.8 100% Positive

b L2H 42.5 ± 3.5b 2.4 ± 0.10b 49.5 ±3.5 80% Negative

2 C Ph2SnfL ]2 34.0 ± 4.8" 1.2 ± 0.12° 30.0 ± 3.2 95% Negative

2 b c Ph2SnfL lCl 38.0 ± 3.6 1.6 ± 0.14 33.6 ±5.5b 91% Negative

b Ph3Sn[L] 35.0 ± 4.2° 1.3 ± 0.18 31.4 ± 6.1° 92% Negative

Values are expressed as mean ± S.E., ap < 0.001, bp < 0.01, cp < 0.02, dp < 0.05

143 Vol. 31, Nos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

6.2.4. Novel Chiral Organotin(IV) Complexes ofBipyridine These complexes show 50 to 85 percent negative fertility at 15 mg dose levels/ per day (Table 19).

6.2.5. Unsymmetrical Macrocyclic Organotin Complexes Organotin Complexes with Bis(3-oxo-2-butylidene)propane-l,3-diamine (L) The results show that the ligand alone is able to inhibit fertility but, due to the added synergistic effects of the tin complexes, its activity becomes enhanced. The results are grouped under the following headings: • Body and Organ Weights: Body weights of rats were not affected after the tin complexes were administrated. However, the weights of testes, epididymis, seminal vesicle and ventral prostate were significantly decreased . • Fertility Test : The sluggish motile spermatozoa were unable to fertilize normal cyclic females. The test was 65 to 95% negative in rats treated with the compounds. • Sperm Motility: The sperm motility declined significantly after treatment with the compounds. • Sperm Density : The sperm density in testes and cauda epididymis declined significantly after treatment (Table 20). • Biochemical Changes: Total protein and sialic acid contents of testes, epididymis, ventral prostate and seminal vesicle were depleted significantly after treatment with the ligand and its complexes. The acid phosphatase levels of testes, epididymis and ventral prostate were also reduced significantly. A significant decrease in seminal vascular fructose contents was also noticed, whereas the testicular cholesterol contents were increased significantly after the treatment with various compounds (Tables 21 and 22).

Table 19 Effects of organotin(IV) complexes on reproductive parameters on male rats.

Group Treatment Sperm Sperm density million/cm3 Fertility test (%) motility Testes Cauda cauda epididymis epididymis (%) A Control 85.0+2.9 5.0 + 0.60 55.5 + 3.9 100% Positive

Β [L,SnPh3.bipy] 65.0 + 3.5" 4.1+0.63" 45.0+1.0" 50% Negative a C [L2SnPh3.bipyl 60.0 +3.0 3.7 + 0.25" 35.5+2.0" 55% Negative b b b D [L,SnMe2Cl.bipy] 35.0 + 3.0 1.9 + 0.15 25.0 + 2.0 80% Negative b b b Ε [L2SnMe2Cl.bipy] 33.0 + 3.5 2.1 + 0.15 22.0 + 2.5 85% Negative Group Β compared with Group A Groups C, D and Ε compared with Group A Mean + SEM of five animals a = ρ < 0.01 b = p <0.001

144 Chaudhary and Singh Main Group Metal Chemistry

Table 21 Sperm dynamics and fertility test after treatment with the ligand and its complexes.

Sperm motility Sperm density Fertility test Group Treatment Cauda (million/ml) (%) epididymis Testes Epididymis

A Control 80.0 ±5.1 1.95 ±0.10 55.5 ±0.10 99% + ve

Β L 50 ± 3.0b 0.85 ± 0.15b 0.85 ± 0.15b 65% - ve

b b b C [Sn(MacL)Cl2] 40 ± 3.9 0.60 ± 0.10 0.60 ± 0.10 82% - ve

b b b D [CH3Sn(MacL)C5H5N)] 24.0 ± 2.0 0.62 ± 0.12 0.62 ± 0.12 88% - ve

b b Ε [C2H5Sn(MacL)C5H5N] 45.0 ± 3.0" 0.70 ± 0.15 0.71 ±0.15 95% - ve Values means ± SE of seven determinations a = P<0.05 ;b = Ρ <0.001

Table 22 Effects of the ligand and its complexes on biochemical parameters (Total protein and sialic acid) of reproductive organs of male rats.

Gro- Treatment Total protein (mg/g) up Testes Epididymis Ventral Seminal vesicle prostate A Control 225.0 ±15.0 200.0 ± 10.0 245.0 ±10.0 260.0 ± 10.0 Β L 165.0 ±20.0 170.0 ± 190.0 ± 10.0 200.0 ± 15.9b b C [Sn(MacL)Cl2l 120.0 ±150" 125.0 ± 10 150.0 ±6.5" 180 ± 10.0 a b b D [CH3Sn(MacL)C5H5N)] 105.0 ±10.2* 110±8.5 122.0 ± 8.2 108.0 ±9.0 a Ε [C2H5Sn(MacL)C5H5Nl 125.7 ±12.0" 140 ± 10.4 140.0 ± 8.0 160.0 ±8.0 Values means ± SE of seven determinations a = Ρ < 0.05 ;b = Ρ <0.001

7. BIOCIDAL ACTIVITY

A system investigation on the antifungal activity of organotin compounds was started in 1950 at the Institute for Organic Chemistry TNO, Utrecht, the Netherlands. Van der Kerk and Luijten soon found that among organotin compounds of the several possible types,

145 Vol. 31, Nos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

R4S11 R3SnXR2SnX2 RSnX3 (R= hydrocarbon radical; X= anionic group)

some representatives of the type R3SnX possessed a high fungitoxicity. Initially tests were carried out with series tetraethyltin, triethyltin chloride, diethyltin dichloride and ethyltin trichloride. Only triethyltin chloride inhibited the growth of test fungi at concentrations below 10mg/l. Variation of the acid radical had only a minor influence on the activity of triethyltin salts. Subsequent examination of a series of tri-n-alkyltin acetates, on the other hand, showed a considerable influence on the length of the alkyl groups (Table 23). The data given in this table differ somewhat from those given in the original publication. They were obtained in later, careful testing using a prolonged incubation time and a richer culture medium. The most active compounds in the series of tri-n-alkyltin acetates were tripropyl-and tributyltin aceate. They inhibited the growth of the test fungi at concentrations of 1 mg/1 or lower.191 Experiments with unsymmetrical trialkyltin acetates, i.e., compounds in which the tin atom bore mutually different alkyl groups, revealed that not the nature of the individual groups, but the total number of carbon atoms in the three groups was decisive. Dimethyloctyltin acetate, for example, had the same high activity as tripropyltin aceate, whereas both trimethyl tin acetate and trioctyltin acetate had a low activity. For a high antifungal activity, the total number of carbon atoms in the alkyl groups of a trialkyltin compound should be about 9-12.192 In addition to the tri-n-alkyltin acetates, numerous other triorganotin acetates were tested for antifungal activity. Triisoalkyltin acetates had an activity which was comparable to that of the normal isomers.193 Tricyclopentyl- and tricyclohexyltin acetate, however, were more active than the n-alkyl derivatives.194 Triphenyltin acetate had about the same activity as triethyltin acetate. Tri-m-tolyl-and tri-p-tolytin acetate differed little from triphenyltin acetate, but tribenzyl- and tris (2-phenylethyl) tin acetate were somewhat less active. Tri-a-naphthyltin acetate, probably because of its low solubility, did not show any antifungal activity.194 When, through the addition reactions of organotin hydrides to olefins, functionally substituted organotin compounds became available, a number of them, both of the type R,Sn and R3EnX, were tested for antifungal activity. It turned out, however, that in no case did a functionally substituted compound have a higher activity than a comparable unsubstituted compound. On the contrary, in most cases the introduction of a functional group severely reduced antifungal activity, especially, hydrophilic groups had an adverse effect.195

No active compounds were ever found among the types R)Sn, R2SnX2, and RSnX3 in spite of careful screening. The sole exception is diphenyltin dichloride, which inhibits the growth of the fungi mentioned in Table 23 at concentrations of 10-20 mg/1.103 In a few cases in which a compound of the type R(Sn showed some activity, either a compound of the R2SnX was present as an impurity or an easy cleavage of one of the R groups probably occurred. An example of the latter is tributyl (cyanomethyl) tin which easily loses the cyanomethyl group under hydrolytic circumstances.196,197

146 Chaudhary and Singh Main Group Metal Chemistry

Table 23 Antifungal activity of some triorganotin acetates

Minimal concentration in mg/1 causing com plete inhibition of growth of the fungi

R3SnOCOCH3R Botryits allii Penicillium Aspergillus Thizopus Refs. italicum niger nigricans

CH3 200 500 200 500 (99)

C2H5 1 10 2 2 (99) n-C3H7 0.5 0.5 0.5 0.5 (99) n-C4H7 0.1 0.5 1 1 (99) n-C4H9 0.5 0.5 1 1 (99) i- C4H9 1 1 10 1 (99) n- CjH„ 5 2 5 5 (99)

Cyclo- C5H9 0.5 0.5 5 0.5 (100) n- C6H,3 500 500 500 500 (110)

Cyclo-C6HU 20 20 50 20 (239)

C6H5 10 1 0.5 5 (147)

Several other groups of workers have studied the antifungal properties of organotin. Independent research on simple alkyl- and aryltin compounds with a practical aim has been carried out by Baumann198 and Härtel199'200 at Farbwerke Hoechst, Frankfort, Germany. This work has led to triphenyltin acetate. Other workers have extended the above results. In most cases the influence of varying the acid radical in triorganotin salts was studied 11 12. Results at variance with the rules formulated above were only obtained when compounds with highly fungitoxic acid radicals were tested.201,202 The action of the organotin compounds at the low concentrations employed in the tests is fungistatic rather than fungicidal. The mode of action of the organotin compounds is still not understood, although it has been suggested193,l97that inhibition of oxidative phosphorylation in the case of the trialkyltin compounds may be the cause of the observed inhibition of fungal growth. The differences in activity among the several trialkyltin compounds might then be attributed both to differences in intrinsic activity on the enzyme system and to differences in permeability into the cells. Permeability in its turn may be dependent on the partition coefficient of the organotin compounds between water and lipids. Antibacterial tests with organotin compounds have been carried out by Kaars Sijpesteijn.109 "°Organotin compounds are, in general, much more active towards gram-positive bacteria like Bacillus subtilis, Mycobacterium phlei and Streptococcus lactis than towards gram-negative ones like Escherichia coli and Pseudomonas fluorescens. The most active compounds, inhibiting growth of the gram-positive species at 0.1-

5 mg/1, again belong to the type R3SnX Among the trialkyltin acetates maximal activity is associated with the propyl and butyl compounds, although tripentyltin acetate is still, highly active against Mycobacterium phlei. Triphenyltin acetate is as active as the most active trialkyltin acetates.

147 Vol. 31, Nos. 3-4, 2008 Organotin Compounds: Perspectives and Potential

It is remarkable that, for the gram-negative bacteria, triethyl-and tripropyltin aceate are the most active trialkyltin acetates. They inhibit their growth at 20-50 mg/1. Dipropyl-, and dipentyltin dichloride have no antifungal properties, but they inhibit the growth of gram-positive bacteria at a concentration of 20-50 mg/1. Trialkyltin compounds have also been tested against pathogenic bacteria, notably staphylococcus aureus (gram-positive) and some Pseudomonas species (gram-negative). The results205,206confirm the trends signalized above. As to the mode of action of the organotin compounds against bacteria, the same remarks can be made as in the case of their action against fungi. It is supposed 103110 that the triorganotin compounds act by their inhibition on enzymes containing thiol groups. Evidence for the latter has recently been presented. The fungicidal activity of the ligand hydrazine carbothioamide and its tin complexes have been reported81' 83. The need for further study and research in the field of chemotherapy has been felt with a view to develop more and more drugs with high efficacy against a variety of pathogens. Besides, investigations into the modus operandi of existing drugs have also been carried out to facilitate the study of microbiology. The exclusive characteristics of non-transition and transition metal chelates with their applications in multispheres have opened new vistas in the field of inorganic biochemistry. We have reported111"115 some derivatives of tin(IV) with biologically active ligands such as sulphonamide imine and study their activity in vitro as well as in vivo against a number of pathogenic fungi and bacteria The results show that the activity is enhanced on undergoing chelation. It is a well known fact that the concentration plays a vital role in increasing the degree of inhibition. As the concentration increases, the activity increases. The fungicidal activity was better as compared to the bactericidal activity

FUTURE PROSPECTS

The importance of ligands in modifying the biological effects of metal based drugs cannot be overestimated. Ligands can modify the oral systemic bio-availability of metal ions, can assist the targeting specific tissues or enzymes and can deliver, protect or sequester a particular metal ion, depending on the requirements, for the therapy and diagnosis. To summarize, we can state that several organotin compounds exhibit rather promising in vivo and in vitro nematicidal, insecticidal and antifertility activity. However more work has to be done on the synthesis and testing of organotin molecules that might become useful nematicidal, insecticidal and antifertility agents in the future.

ACKNOWLEDGEMENT

I (Dr. Ashu Chaudhary) would like to thank all my coworkers who prepared, purified and characterized the compounds reported in this article and also especially Prof. A.K. Singh for the acquisition of the Mossbauer spectra that were not discussed in this paper but that are essential for the characterization of the compounds. This research was supported by C.S.I.R, New Delhi.

148 Chaudhary and Singh Main Group Metal Chemistry

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