SYNTHESIS AND BIOLOGICAL ACTIVITY EVALUATION OF NATURALANTIFUNGALS AND THEIR ANALOGUES

Abstract of the work The need to develop new fungicides remains a major driving force, as fungal plant pathogens continue to develop resistance against existing fungicides at great speed, and also because new disease situations continually arise. The science of natural products has advanced significantly in recent times, and many compounds derived from nature have found a use in crop protection. Natural products, with their tremendous structural diversity, are an important source of new toxophores. If their properties allow and if sufficient quantities can be obtained from natural sources or by synthesis, such compounds may be used directly as agricultural chemicals. Alternatively, they may constitute useful starting points for the synthesis of analogues with improved biological and physical properties. The aim of this PhD work was to synthesize naturally occurring antifungal compounds and to test their biological activity. Three compounds were chosen in the literature: Farinomalein, Epicoccamide and Harzianic acid, as their biological activity and novel chemical structure made them attractive targets for chemical synthesis. Thus, during the PhD work, efforts were made to synthesize the natural compounds and their analogues. First, a practical and convenient synthesis of the fungicidal natural compound Farinomalein was carried out starting from readily available ethyl 3-methyl-2-oxobutyrate and triethyl phosphonoacetate, employing a Horner-Wadsworth-Emmons condensation as the key step. The antifungal activity of a series of analogues of farinomalein was evaluated against Cladosporium cladosporioides. Changing the linear side chain into a branched one seemed not to be crucial for the activity, whereas increasing the number of side chain carbons significantly affected the antifungal activity. Efforts towards the first total synthesis of Epicoccamide D were also made. Epicoccamide D exhibits antifungal activity; moreover, it shows weak to moderate cytotoxicity towards HeLa a cell lines (CC50 17.0\ub5M) and good antiproliferative effects on mouse fibroblast (L-929) and human leukaemia cell lines (K-562) with inhibition of growth (GI50) of 50.5 and 33.3\ub5M, respectively. Finally, a synthetic strategy of Harzianic acid was developed. Harzianic acid has significant antifungal and plant growth promotion effect, which makes it a potential lead for the design of new antifungals. The evaluation of the biological activity of this intermediates and completion of total synthesis of harzianic acid is in progress. During the PhD an expedient synthesis of 3,7-diaryl-1,4-dihydro[1,2,4]triazolo[5,1-c][1,2,4]triazines was also developed. It was carried out in three steps from 3,5-dibromo-1H-1,2,4-triazole.The reactions were conducted under easy-to-perform, mild conditions with moderate to good yields. The synthesis affords easy entry to previously unreported heterocyclic compounds of potential pharmacological and agrochemical interest

Synthesis of natural maleimides farinomaleins C–E and evaluation of their antifungal activity

A practical and convenient synthesis of naturally occurring farinomaleins C\u2013E was achieved starting from readily available ethyl 3-methyl-2-oxobutyrate and triethyl phosphonoacetate. The key steps of the sequence included a Horner\u2013Wadsworth\u2013Emmons condensation to obtain the precursor farinomalein A and coupling with suitable alcohols to install the chain. The synthesis of farinomalein D has been achieved starting from (R)-isopropylideneglycerol on the basis of which the S configuration was assigned to the natural compound. The antifungal activity of the synthesized compounds was evaluated against Cladosporium cladosporioides

Improved synthesis of farinomalein and its analogs

A practical and convenient synthesis of the fungicidal natural compound farinomalein is described starting from readily available ethyl 3-methyl-2-oxobutyrate and triethyl phosphonoacetate, employing a HornerWadsworthEmmons condensation as the key step. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications (R) to view the free supplemental file

A synthetic approach to 3-acyltetramic acid and application to the total synthesis of Epicoccamide D

Naturally accoutring 3-acyltetramic acids1,2 (3-acylpyrrolodin-2,4diones, 1) are core structural skeletons that have been found in various biological active products, such as magnesidin A(antibiotic activity)3a, tenuazonic acid (antiviral and antitumor activity)3b, Sch 213766 (anti-HIV activity)3C, the melophlins (antitumor activity)3d, and the macrocidins ( herbicidal activity). 3f Three new tetramic acid derivatives, epicoccamides B-D, have recently been isolated from an Epicoccum sp. associated with the tree fungus Pholiota squarrosa. The derivative with the longest chain, epicoccamide D, induces morphogenesis and pigment formation in surface cultures of fungus Phoma destructive at concentration of 1.7nM. Despite the great significance of 3-acyltetramic acids, the development of a comprehensive and general protocol for the synthesis of this type of compounds has substantially not been achieved.4-10 We have developed an efficient synthetic sequence for the construction of N-methyl- 3-acylteramic acids. The strategy was applied to the synthesis of the natural compound Epicoccamid

Synthesis of the antifungal natural compound Farinomalein and analogues

Recently, a three-step synthesis of Farinomalein has been reported by Miles and Yan.[2]. However, the Authors themselves state that their synthesis is difficult to scale-up due to the use of hazardous and expensive oxidant Dess-Martin periodinane. Here we report a different synthetic approach to Farinomalein, developed in four steps with high yield and without using any hazardous chemical. The new synthesis is flexible and convenient, starting from readily available ethyl 3-methyl-2-oxobutyrate and triethyl phosphonoacetate and employing a Horner-Wadsworth-Emmons condensation as the key step. The procedure was scaled up to 10 g batches. The methodology was used to prepare different analogues, to support structure-activity relationship studies. The antifungal activity of Farinomalein and its analogues was tested against various fungi

Efficacy and safety of fixed dose combination of Sitagliptin, metformin, and pioglitazone in type 2 Diabetes (IMPACT study): a randomized controlled trial

Abstract Background Due to the progressive decline in β-cell function, it is often necessary to utilize multiple agents with complementary mechanisms of action to address various facets and achieve glycemic control. Thus, this study aimed to evaluate the efficacy and safety of a fixed-dose combination (FDC) of metformin/sitagliptin/pioglitazone (MSP) therapy vs. metformin/sitagliptin (MS) in type 2 diabetes mellitus (T2DM). Methods In this phase 3, multicenter, double-blind study, patients with T2DM who exhibited inadequate glycemic control with HbA1c of 8.0–11.0% while taking ≥1500 mg/day metformin for at least 6 weeks were randomized to receive either FDC of MSP (1000/100/15 mg) or MS (1000/100 mg) per day for 24 weeks. The primary outcome measure was the change in HbA1c, and secondary outcomes included changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and body weight from baseline to 24 weeks along with safety and tolerability. Results Among the 236 patients randomized, 207 (87.71%) successfully completed the study. All baseline characteristics were comparable between the FDC of MSP and MS groups. There was a subsequent significant reduction of HbA1c in FDC of MSP (− 1.64) vs. MS (− 1.32); between groups was [− 0.32% (95% CI, − 0.59, − 0.05)], P = 0.0208. Similar reductions were found in FPG [− 13.2 mg/dL (95% CI, − 22.86, − 3.71)], P = 0.0068, and PPG [− 20.83 mg/dL (95% CI, − 34.11, − 7.55)], P = 0.0023. There were no significant changes in body weight. A total of 27 adverse effects (AEs) and one severe AE were reported, none of which were related to the study drug. Conclusion The FDC of MSP demonstrated significant efficacy in managing glycemic indices and could serve as a valuable tool for physicians in the management of Indian patients with T2DM. Trial registration Clinical Trials Registry of India, CTRI/2021/10/037461