INTRODUCTION:

The uses of pesticides, herbicides, defoliants, growth regulators, fungicides and insecticides in agriculture can prevent the loss of food crop production. Being a well populated country, the country needs more production of chow to fulfill the requirements. Since the near worldwide ban of chlorinated insecticides DDT on agriculture uses which began in the 1970's and 1980's, [1] the search for efficient and secure insecticides that exhibit little bio-persistence and low toxicity to birds, mammals, and aquatic life has intensified. The requirement for safe insecticides is driven by a continuing need to control malaria and to feed a growing world population. Indeed, it has been estimated that up to 15% of annual global food crops are lost to insects. [2]. The hunts for a more reliable and suitable drug is always attractive and challenging. A number of drugs containing simple heterocyclic or a combination of different heterocyclic moieties have been in use now-a day.

Till 1940s inorganic substances, such as sodium chlorate and sulphuric acid, or organic chemicals obtained from natural sources were still extensively used in pest manage. However, fewer pesticides were by-products of coal, gas production or other industrial processes.

Thus, early organics such as Nitro phenols, chloro-phenols, cresol, naphthalene and petroleum oils were used as fungicides and insecticides, even as ammonium sulphate and sodium arsenate were used as herbicides. The disadvantage of many of these products was their high rates of application, lack of selectivity and phytotoxicity this period also saw the introduction of the triazole, morpholine, imidazole, pyrimidine and di-carboxamide families of fungicides [3,4].

The azole moiety is a significant and frequent insecticidal, agrochemical structural characteristic of many biologically active compounds such as cytochrome P450 enzyme inhibitors [5]and peptide analog inhibitors [6]. The lead 1, 2, 4-Triazoles constitute an important class of heterocyclic compounds; their derivatives posses varied types of biological activity and are used as fungicides, insecticides, herbicides [7], defoliants and growth regulators [8-10]. Further, the disubstituted 1, 2, 4-triazole derivatives were also reported to show antifungal, insecticidal, herbicidal and anti-inflammatory properties which were similar to 1H-1, 2, 4-triazole derivatives [11-13].

Azole or conazole fungicides correspond to a large group of substances extensively used in agriculture for the protection of crop plants and pharmaceutically in the treatment of various fungal diseases. They are synthetic compounds that can be classified into imidazole or triazole, depending on the number of nitrogen atoms in the five-membered ring. Some fungicides from the imidazoles groups are ketoconazole, miconazole and clotrimazole. In the group of triazoles we can quote the itraconazole, fluconazole, flusinazole, triadimefon and flutriafol. Further, the triazole can be divided into two groups: triazole antifungal drugs, that comprise the fluconazole, voriconazole, isavuconazole, itraconazole, etc., and triazole plant protection fungicides like tebuconazole, triadimefon, triadimenol, paclobutazol and flutriafol are most commonly used. A number of triazoles are broad spectrum antifungal agents used as pesticides and pharmaceuticals [14,15]. They inhibit the biosynthesis of ergosterol, which is an essential component of fungal membranes. Triazole antifungal agents are extensively used. The target site of all triazoles in fungi is the enzyme erg11/cyp51. Fungicidal activity is a consequence of the direct inhibition of lanosterol-14-alpha-demethylase activity of CYP51, which is an essential step in ergosterol biosynthesis. Ergosterol is a derivative of cholesterol and is required for membrane fluidity and the integrity of fungal cell walls [16]. Triazoles act by binding to the heme iron in CYP51, thus inhibiting its activity which is detrimental to fungal growth (Zarn et al., 2003). The CYP51 gene is functionally conserved and is the only member of the CYP family having catalytically identical orthologues in plants, fungi, prokaryotes, and higher species. It encodes for lanosterol demethylase activity, critical for sterol biosynthesis in mammals. In humans, the sterol 14-demethylase, i.e. CYP51, is expressed in many different tissues [17].

Specifically, 3-amino-1, 2, 4-triazole is a widely used as a non-selective herbicides and defoliant of cotton, although in low concentration it may produce growth. The 3(5)-amino-1, 2, 4-triazoles are known to be biologically active compounds. For example, the 3-amino-1, 2, 4-triazole itself has been used as the pesticide (Amitrole) and 3, 5-diamino-1, 2, 4-triazole (Guanazole) is an antitumor drug that inhibits ribonucleotide reductase and DNA synthesis. [18]

Amitrole Guanazole

1 2

Five types of substituted 1-imidoyl-(1H)-1, 2, 4- triazoles have been reported by S. Stankovsky et al [19]. All the substituted compounds were prepared by simple nucleophilic substitution of the known imidoyl chloride with the sodium salt of triazole and screened those synthesized compounds as Herbicidal, fungicidal, and growth-regulating properties, on selected plants. None of the compounds affected growth characteristics of tested plants. Among the synthesized compounds very few have shown noticeable fungicidal activity and showed various degrees of herbicidal activity on all tested plants

3 4

Sanchez-Soto et.al [20] was involved in some research projects on environmental problems concerning pesticides and their application in agricultural soils. They have investigated a thermo analytical study of 3-amino-l, 2, 4-triazole (ATA), using simultaneous DTA-TG in nitrogen flow in order to know the thermal behavior and stability of ATA. These techniques have been further complemented using evolved gas analysis and mass spectroscopy (EGA-MS). A kinetic study has been also carried out applying different models to DTA-TG data. In this study, they have observed two different stages of ATA decomposition: after the first decomposition step, a mixture of compounds is obtained, according to MS data, being the principal component a compound of molecular weight 126. It is formed by a first order reaction mechanism, according to the kinetic study, with Ea= 124+8 kJ.mol^-1.At about 735⁰C the second decomposition step takes place with the evolution of HCN and NH₃, being the final weight loss 96%.

5 5A 6

Eight novel 1, 2, 4-triazole derivatives were synthesized and their insecticidal activities were reported by Bing Chai et.al [21]. The synthetic conditions of the title compounds were investigated, such as temperature, time and base. The temperature had great effect on the yield of the title compounds. The low temperature will prolong the reactive time; otherwise, the by-product will become more when the temperature is beyond 40^oC. At the temperature about 30^oC got the satisfied yield. The effect of strong base was better than that of weak base clearly. The compounds of 9d, 9e and 9g showed insecticidal activity against Aphis rumicis Linnaeus. They have the insecticidal rate 45%, 38% and 30% of the concentration of 500ppm. The studies further showed that the insecticidal activity decreased clearly when the concentration was decreased.

Ravindra R Kamble and Belgur S Sudha [24] have reported a simple and high yielding method for the integration of a 1, 2, 4-triazole ring with 1, 2, 4-triazine- 5-one (12a–j) from 3-arylsydnones The structures were proved by their spectral data and screened for antihaemostatic activity. Tail bleeding time in conscious mice was used to determine antihaemostatic activity of title compounds. Antihaemostasis results revealed that the final derivatives do not show activity more than or equal to standard drug indomethacin. Only derivatives containing the C=S group with p-bromophenyl substituent 12j and p-chlorophenyl substituent 12i showed considerable antihaemostatic activity.

A Potential manufacturing routes to three halogenated 2-thiophenecarboxylic acid derivatives 4-bromo-3-methyl-2-thiophenecarbonyl chloride (13), 3, 4, 5-trichloro-2-thiophenecarbonyl chloride (14), and 3, 4, 5-trichloro-2-thiophenecarbonitrile (15) from commercially available thiophene successfully developed by John W. Hull Jr et.al [25], cemented the way for the development of viable commercial processes for 16 and 17, members of a new class of 2, 6-dihaloaryl 1, 2, 4-triazole insecticides that exhibit selective activity against mites, aphids, and whiteflies coupled with low mammalian toxicity.

Synthesis, antimicrobial and insecticidal activity of some 4H-1, 2, 4 traizole derivatives have been reported by Nidhi Gautam and O P Chourasia [26]. For the preparation of some biologically active 3- substituted phenyl, 4H-1, 2, 4 triazole derivatives, they have used 1-(substituted benzylidene) semicarbazide as a precursor. The several synthesized derivatives have been screened for their antibacterial activity against Bacillus subtili, E. coli. Saureus and K.pneumoniae. Antifungal efficacy against Aspergillus flavus, Fusarium oxyporum, Aspergillus niger and Trichoderma viridae and insecticidal activity against Periplaneta Americana. Synthesized compounds having halogen and hetero atoms in their structure exhibited more antibacterial and antifungal activity in comparison to the antibacterial standard drug streptomycin and antifungal drug Griseofulvin. Few have shown average activity in both the cases. In case of insecticidal activity the few synthesized compounds have been more active than the used standard drug and can be used as insecticidal agents.

Ruan et al.[27] have reported the Synthesis of new 1-(2, 4-dichloro phenyl)-3-aryl-2-(1H-1, 2, 4-triazol-1-yl) prop-2-en-1-one derivatives and their antifungal activity against three pathogenic fungi, G. zeae, F. oxysporium, and C. mandshurica by the poison plate technique.

A series of novel 1-(2, 4-dichlorophenyl)-3- aryl-2-(1H-1, 2, 4- triazol-1-yl) prop-2-en-1-one derivatives were obtained through aldol condensation. In order to enhance the reactivity of nucleophilic component of the reaction, they converted 1H-1, 2, 4-triazole into its corresponding sodium salt and then used different solvents and catalysts to obtain the compounds in much higher yield under relatively mild conditions. Amongst the tested products, compound 19 showed an antifungal activity level similar to that displayed by Hymexazol against G. zeae, F. oxysporum, and C. mandshurica.

Monica Gupta [28]. have reported a simple, fast, cost effective and environment-friendly comparative procedure for the one-pot synthesis of antifungal active 8-methyl-3, 6, 8- trisubstituted-7H, 9H-[1, 2, 4]triazolo[4, 3-b][1, 2, 4] triazepines via condensation of 5-aryl-3, 4-diamino-1, 2, 4-triazole and acetophenone using ionic liquid under stirring in an oil-bath pre-maintained at 80°C.

Some of the synthesized derivatives were tested for their antifungal activity against Aspergillus niger, Aspergillus flavus, Rhizopus species and Pencillium species by paper disc method against two concentrations 500 μM and 1000 μM was compared with that of standard fluconazole. The result data revealed that the compounds 20a, 20b, 20c and 20d showed excellent activity against Pencillium species at 1000 μM and good at 500 μM whereas Aspergillus niger, Aspergillus flavus and Rhizopus species at 500 μM as well as 1000 μM showed fair to good activity.

The Synthesis and insecticidal activity of 1, 2, 4-triazolo-thiazolidin-4-one derivatives have reported by Vijay Kumar Tirlapur and Tukram Tadmalle [29]. Fourteen novel triazole derivatives were synthesized and their insecticidal activities were tested. All the synthesized compounds bioactivity was screened by the contact poison and stomach poison method. The compounds of 21b, 21d, 21e, 22b, 22d and 22e showed insecticidal activity against Heliothis armigera at the concentration of 500ppm. Finally it’s concluded that the insecticidal activity depends on drugs concentration as the insecticidal activity decreases clearly when the concentration was decreased.

Due to the high incidence of plant mortality and the lack of effective control methods, Tang et al [30] have designed an active amide structure and synthesized a series of novel amide derivatives containing a triazole moiety to discover new bioactive molecules and pesticides that can act against fungi and bacteria. A series of novel amide derivatives containing 1, 2, 4-triazole moiety were synthesized through the reaction of intermediate 23 with different acyl chlorides and anhydrous potassium carbonates in anhydrous tetrahydrofuran at 50°C, using 2, 4-dichloroacetophenoneas as a starting material. Antifungal activity test showed that some of the synthesized compounds exhibited moderate antifungal activity against tested fungi at 50 mg/L. Compound 24u displayed more potent antifungal activity against P. sasakii and G. azeae than hymexazol. Antibacterial activity results showed that some of the synthesized compounds exhibited high antibacterial activity against R. solanacearum at 200 mg/L. Compounds 4m and 4q displayed high antibacterial activity against R. solanacearum, with 71% and 65% inhibitory rates, respectively.

Saad R. El-Zemity et al [31]. have reported a series of (1H-1, 2, 4-triazole -1-ylmethyl) phenols, anilines, N-alkyl anilines, and N, Ndialkyl anilines and evaluated them for in vitro antifungal and antibacterial potential. The results discovered that 1, 2, 4-triazol-1-ylmethyl) phenols were much more fungitoxic than 1, 2, 4-triazol-1-ylmethyl) anilines against all tested fungi. Compounds 25d, 25e and 25f exhibited very high fungitoxic effect. The un-substituted phenols showed low fungicidal activity. Where N-substituted anilines (26b-e) showed higher fungicidal and bactericidal action than that of the un-substituted compound (26a).

Microwave assisted synthesis, antifungal activity and DFT theoretical study of some novel 1, 2, 4-triazole derivatives containing the 1, 2, 3-thiadiazole moiety has reported by Na-Bo Sun et al.[32] The seventeen novel derivatives has been prepared by multi-step reactions under microwave assisted conditions and screened for antifungal activity against Corynespora cassiicola, Pseudomonas syringae pv. Lachrymans, and Pseudoperonospora cubensis, and the results showed that some of the synthesized compounds displayed good fungicidal activities.

Synthesis and biological activity of substituted urea and thiourea derivatives containing 1, 2, 4-triazole moieties have been reported by Bedia Kocyigit-Kaymakcioglu et al [33]. A series of novel thiourea and urea derivatives containing 1, 2, 4-triazole moieties were synthesized and evaluated for their antifungal and larvicidal activity. Triazole derivatives 30a–e and 31a–e were synthesized by reacting thiocarbohydrazide with thiourea and urea compounds 28a–e and 29a–e, respectively, in a 130–140 °C oil bath. All compounds were evaluated for antifungal activity against plant pathogens, larvicidal and biting deterrent activity against the mosquito Aedes aegypti L. and in vitro cytotoxicity and anti-inflammatory activity against some human cell lines. Phomopis species were the most sensitive fungi to these compounds. Compounds 28b, 28c, 30a and 31e demonstrated selectively good activity against Phomopis obscurans and only 28b and 31e showed a similar level of activity against P. viticola.

Current aspects of triazole derivatives:

Current FDA-approved triazole analogues (fluconazole, itraconazole, posaconazole, and voriconazole) are extensively prescribed for invasive fungal infections, and numerous other triazoles are in development (albaconazole, isavuconazole, ravuconazole). Although the relative risk of liver toxicity with triazoles appears low, dose-limiting toxicities and pharmacokinetic drug-drug interactions may complicate the use of these agents. New corrosion inhibitors, namely 3-vanilidene amino 1, 2, 4-triazole phosphonate (VATP) and 3-anisalidene amino 1, 2, 4-triazole Phosphonate (AATP) was synthesized and the action along with biocide on corrosion control of copper in neutral aqueous environment has been studied.

CONCLUSION:

The study revealed that 1, 2, 4 triazole as a lead potent anti fungal agent in both mammalian and plant fungi. And supplementary conclusion was 1, 2, 4- triazole ring fused with other heterocyclic system showed better insecticidal and fungicidal activity. So further study is required on 1, 2, 4 triazole and their fused structure with other heterocyclic compounds for better activity.

ACKNOWLEDGEMENT:

The authors are grateful to the management and Principal of Pulla Reddy Institute of Pharmacy, Annaram Sangareddy, Hyderabad., Telangana, India for making available all the facilities.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 26.04.2019 Modified on 30.05.2019

Research J. Pharm. and Tech. 2019; 12(10):5091-5097.

DOI: 10.5958/0974-360X.2019.00882.5