SYNTHESIS AND PHYSICO CHEMICAL STUDIES OF SULPHUR AND NITROGEN COMPOUNDS WITH POTENTIAL BIOLOGICAL ACTIVITY

Abstract

The turn of century has witnessed the development and great expansion of research in medicinal chemistry all over the world. The research workers in this fascinating field are still confronted with the unabating need for unsolved therapeutic problems. Still suitable curative and corrective agents remain to be developed for common diseases like tuberculosis, cancer, diabetes etc. Adequate drugs which can "be used as anesthetics with little or no toxicity are still lacking. A vast amount of biological and chemical work has been done in the search for useful agents. Interest in this field has been stimulated by improved methods of biological test procedures and the ensuing demands for new corrective and curative agents. Further impetus to research work in this direction was given by tackling these problems from the purely physico-chemical angle. Elucidation of the structure of many complex natural products including many metabolites; the study of electro-chemieal behaviour of these products; and the role of metal ions (both alkali and alkaline earth metals and transition elements) in controlling their physiological activity immensely contributed to the solution of chemotherapeutic problems. Fundamental studies on the synthesis of new types of chemotherapeutic agents have paved the way for better research in the field of biology and medicine. With the combined efforts >- 2 of chemists, biochemists and biologists (bacteriologists, mycologists, entamologists etc.), it has been possible to new truths correlating chemical structure with biological activity. A new scientific discipline named as 'Structure and Activity' has thus come to stay. It is a tribute to human pursuit of knowledge and bis untiring efforts that he is not only developing new and efficacious drugs but finding new ones for curing dreadful diseases such as cancer, diabetes, cardiac abnormalities etc. The elucidation of the structure of such complex molecules such as penicillin, vitamin B1, proteins etc. are the landmark in the history of chemistry and their discovery provided the long awaited impulse and encourage ment for more concentrated efforts in the field of medicinal chemistry. Sulphur compounds in medicine The importance of organic sulphur compounds is mainly due to their remarkable pharmacological activity and which is mainly due to the presence of >N-CS-N< group. From the chemotherapeutie point of view these compounds have been used as 12 ^ A antituberculous , hypnotics , loeal anesthetics , analgesics4 and antbelintic agents, specially for trypanosomes , blood 6 7ft parasites also as fungicides, insecticides , rodentieides and as antispasmodic9110. Recently antiviral11'12 and anti- 13 radiation activities have also been observed in some of the derivatives. Some derivatives of thiourea are known to possess hypoglycemic activity . 3 The epoch making discovery 5 of the tuberculostatic activity of thiosemicarbazone was the outcome of a systematic study of the sulphonamide drugs in tuberculosis. Modified thiosemicarbazones such as thiosemiearbdzone of p-acetamidobenzaldehyde (also known as tibione ) was found to be orally active against experimental infections in animals, its activity being comparable to streptomycin. The discovery of the tuberculostatic activity of isoniazid and its derivatives was yet another forward step in this direction. Isoniazid is 16 highly active in small doses . Clinical application has shown it to be relatively non-toxic and well tolerated17""19. A large number of compounds have been synthesised by various substi tution in the structure of isoniazid, but surprisingly none of these were found to be superior to the parent compound. The discovery of definite in vitro antitubercular activity of thiocarbamide, its phenyl or sulphanilyl 20 derivatives , and the out standing tuberculostatic properties of N,N'-di-(p-n-butoxyphenyl)thiocarbamide has considerably revived interest in the study of thiocarbamide derivatives. It has been observed that some of the N,N'-dialkoxythiocarbanilides (especially 4,4'-diisoamyloxythiocarbanilide) are effective 21 against human leprosy and in mice infected with influenza 22 virus . Recently it has been found that some derivatives of 2-aminobenzothiazoles and 2-aminothiazoles, oxidised and cyelised products resulting from thioureas, possess considerable local anesthetic activity 5» *. In recent years several reports have been published concerning the biological potency of various substituted thioureas . These reports suggest that further investigation on tbiocarbanilide might lead to the discovery of new chemotherapeutic agents. Importance of Polarographic studies in biological processes The importance of electrochemical data in eluci dating the biochemical and physiological processes in the human system is well established* Compounds of medicinal importance influence these processes, through many complicated physico-chemical reactions. These reactions, although difficult to unravel, have one point in common, viz., that they are electron transfer reaction*and therefore, a knowledge of their redox behaviour is of primary importance. Long before the advent of polarography, potentiemetric methods were used for ascertaining the redox behaviour but it has had its limitations due to the non-availability of suitable electrodes to meet a particular situation, erratic performance in non aqueous media, irreversibility of the system under investigation, A real break through was achieved only when polarographic technique was applied to study the electrochemical properties of sueh compounds. Contrary to potentiometric methods, the polarographic method has the extra advantage of its capability of being used in solutions containing inorganic ions over a wide pH range. Furthermore the method is able to analyse micro quantities of substances and it is, therefore, very useful for compounds of biological importance which are usually made available in small quantities. Quite a few applications of polarography in the field of biology and medicine have been cited in the chemical 5 literature. Apart from determining the redox potential, it has been used to distinguish the different pathways in biological processes, in ascertaining the structural characteristics of compounds, in the estimation of drugs and in clinical diagnosis. Direct or indirect application of this technique in medicinal and biological chemistry is thus amply Justified. An example where the knowledge of redox potential can be fruitfully employed to understand the mechanism of biological process is worth quoting. The chemical oxidation of urie acid produces either allantoin or alloxan but not both. However, the electrochemical oxidation of uric acid involves a 2e oxidation to a primary short lived- dicarbonium ion, which undergoes simultaneous transformations including hydrolysis leading to an allantoin precursor and hydrolysis leading to 26 alloxan and urea „ The plausibility of postulating an intermediate which can undergo transformation to either allantoin or alloxan suggests that the oxidation of uric acid by any method produces a common intermediate whose subsequent transformations-and consequently the ultimate products obtained - were determined by experimental conditions. An analogous reaction path has been postulated27 to explain the results for the enzymatie uricase oxidation of uric acid, reflecting an interesting parallelism between the two types of oxidation. The electrochemical oxidation of adenine initially follows the same path as the enzymatic oxidation with xanthine oxidase, but further oxidation and fragmentation of the purine occur28. «? Metal complexes vis-a-vis biochemical reactions The fact that metal complexes play an important role in biochemical processes is being gradually realised. Extensive investigations during the last three decades have shown that not only their complexes control a variety of enzyme catalysed reaction but they are involved in other phenomenon also. Lately for example, new biochemical concepts are being developed in which metal complex formation is envisaged in curing of diseases. Some ©f these concepts are incorporated in recent reviews such as "The Effects of Chelating Agents on Organisms"29, "Chelation in Medicine"50, "Metal Binding in Medicine"51, "Metal Chelates in Biological 32 •2-ar Systems" , and "Structure and Bonding in Biochemistry"55. The concept that metal complex formation is a part and parcel of normal life processes is gaining ground rapidly. Another example which strongly bears out what has been said above is the existence of iron-sulphur clusters in natural systems. Recently an important new class of melalloproteins, the nonhaem iron-sulphur proteins have been isolated from organisms varying widely in evolutionary development, including aerobic, anaerobic and pbotosynthetic bacteria, algae, fungi, higher plants, and mammals. Holms and coworkers have synthesised iron-sulphur complexes of the type TFe?Sp(SR)~| "*2 r~ —, —p — and [Ee4S4(SR)4| (where R stands for an amino acid or a peptide) and have established their importance as structural models and indicators of oxidation levels of active sites in nonheam iron sulphur proteins, Polarographic studies in ? non-aqueous media has demonstrated the four membered electron transfer series with reversibility most satisfactorily established for the 2~/3-couple40. [Fe4S4(SR)4]*- 4r* [^(SR^] 3~ ^ [*V4(tt>4] 2~ 4—^[Fe4S4(SR)4]1- Along with alkali and alkaline earth metals the transition metals sueh as mangnese, cobalt, copper, zinc, iron, niekeg, molybdenum and platinum have been extensively investigated with regard to their biochemical role. Mangnese exists in solution in oxidation state(II) and (III) if complexed. It is essential for several enzymes such as isoeitrate dehydrogenase, malic enzyme and pyruvate decarbo xylase. Iron is the transition metal that occurs in the highest concentration in our systems. Depending upon the complexing ligand attached to the iron, the metal may be divalent (for example hemoglobin), trivalent (e.g. oxidases). Cobalt is best known for being the central ion in oobalamins and cobamides (vitamin B12 cobalt(III)). Copper, using oxidation states(l) and (II), and cuproproteins can carry oxygen (for example hemocyanin) with the exception of iron, copper is the best catalyst for such oxidation-reduction processes. 2inc exhibits but one oxidation state in vivo but, nevertheless, it is still essential to several aetaiioenzymes. Molybdenum, however, does enter into redox reactions (V-» vi) and even the (III) and (IV) oxidation states are suspected of being involved4"1. Its most notable role is in the xanthine and purine oxidases in milk (two Mo and eight Fe). It is significant to note that molybdenum (atomic number 42) is the heaviest essential element in vivo. Compounds of the elements of group VIII in the d block have been particularly successful in destroying cells : (a) Livingstone has reported a series of nickel, palladium and platinum dialkyldithiophosphates which are capable of reducing mice tumors to 69#* . (b) Rosenberg has reviewed45 a range of platinum complexes that are capable of being bacteriocidal if negatively charged (for example, hexachloroplatinate( lV) anion), of blocking the division but not the growth of a cell if neutral, and of being antitumor and 44-46 lysogenic if cis, (for example, cis-dichlorodiammine platinum(Il). The complexes produced increased survival rates, complete cures, and future immunity to tumors introduced by transplants, 46-48 carcinogens, or viruses^ * . Further, they had promising synergistic effects when combined with other drugs, and any cytotoxic damage produced in normal tissue was reversible4"9. Thin mode of action appears to be through forming intrastrand links in a DNA chain, (c) Similar characteristics are to be expected for rhodium and irridium complexes4"9""50. The important chemistry of nucleie acid-transition metal ion bonding has been reviewed by Weser51.