An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

Abstract

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acidchlorides (5a-d) using HSnBu₃.

Introduction

United Nations Program On HIVAIDS (UNAIDS) estimates approximately 35.2 million people worldwide are living with HIV and more than 25 million people have died of AIDS. Thus so far, 28 anti-HIV drugs have been licensed by the United States Food and Drug Administration (FDA). Most of these drugs belong to two categories: reverse transcriptase inhibitors (RTI) and protease inhibitors (PI). Combined application of these antiretroviral drugs has shown significant synergistic effects.¹ However, an increasing number of patients with HIV infection/AIDS can no longer use such drugs as a result of drug resistance and serious adverse effects.² Therefore it is essential to develop novel anti-HIV drugs targeting HIV entry. A recent report³ identified 2-aryl-5-(4-oxo-3- phenethyl-2-thioxothiazolidinylidenemethyl)-furans (A, Fig. 1) with Rhodanine as a core molecule exhibited anti-HIV-1 activity. On the other hand, Rhodanine⁴ and its derivatives possessing hydrogen attached to the nitrogen atom have been patented as fungicides while the compounds containing nitrogen atom⁵ were patented as pesticides, with mention being made of their usefulness as fungicides. 5-Benzylidine-3-pheny-2-thioxo-thiazolidin-4-one core (B, Fig. 1) was shown to inhibit the Jun NH₂-terminal kinase (Jnk) stimulatory phosphatase-1 (JSP-1).⁶ In addition Rhodanine-based molecules are popular as small molecule inhibitors of numerous targets such as HCV NS3 protease,^7a aldose reductase,^7b,c β-lactamase,^7d UDP-N-acetylmuramate/L-alanine ligase,^7e antidiabetic agents,^7f cathepsin D,^7g and histidine decarboxylase.^7h For the past few years our group has been preparing and evaluating biologically important compounds.⁸ Herein we report the synthesis of a novel class of rhodanine-based small molecule with the aim of investigating their inhibitory properties against JSP-1 and HIV-1 in the low micro molar range.

Fig. 1.

Competitive inhibitor of HIV-1 and JSP-1

5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thiox-othiaz- olidin-4-ones (7a-q) were synthesized by a Knoevenagel condensation of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) derivatives with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehydes (6a-d) using MW irradiation and catalytic amount of 2,2,6,6-tetramethyl piperidine (TMP) in ethanol (Scheme 1). Although other bases (Table 1) can be used as catalyst {e.g,; piperidine, pyridine, N-methyl piperidine (NMP), DBU}, TMP works best. The same reaction under conventional reflux condition using ethanol as solvent gave lower yields (11 to 69%),³ longer time (5 h) and/or compounds required rigorous purification. However the MW reaction provides cleaner reaction, 15 min time and the products only required to be washed with cold ethanol. The yields are good to excellent (Table 3). The optimum temperature and condition for this MW assisted reaction was determined by a series of reaction of 3-phenyl-2-thioxothiazolidin-4-one (3b) and 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a). The results are summarized in Table 1. From this table it is clear that MW irradiation at 90 °C for 15 min in ethanol is the optimum condition for the synthesis of these molecules. All the compounds 7a-q were isolated as single (Z ) isomer and was confirmed by comparing the vinylic proton shift in ¹H NMR with previously reported^3,6 data which appears around δ 8.00 ppm.

Scheme 1.

Schematic representation for the synthesis of 7a-q

Table 1.

Screening of solvents, reaction time and temperature for the synthesis of 7b

Base	Conditiona	Temp (°C)	Time (mins)	Yield b (%)
-	No solvent	90	15	Trace
-	Ethanol	90	15	Trace
Piper idene	Ethanol	90	15	80
TMP	Ethanol	90	15	96
TMP	No solvent	90	15	Trace
DBU / pyrid ine	Ethanol	90	20	20
TMP	Acetonitrile	90	15	76
TMP	Acetonitrile	130	15	15
DBU	Acetonitrile	90	30	Trace
TMP	DMF	90	15	45
	DMF	90	30	10
NMP
DBU	DMF	120- 140	15	Trace
TMP	Water	90	15	Trace
TMP	Water	130	15	Trace
-	Water	130	30	Trace
TMP	Toluene	90	15	Trace
TMP	Isopropanol	90	15	45
TMP	THF	90	15	38
TMP	n-Butanol	90	15	33

^aAll the reaction was carried out in equimolar amount of each compound in 2 ml of solvent at 150 psi pressure.

^bIsolated yield

Table 3.

Reaction of various indole based aldehydes with Rhodanine derivatives

Entry (%)	R1	R2	R3	R4	product	Yielda,b
1	H	H	H	H	7a	95
2	CH3	H	H	H	7b	96
3	CH3	CH3	H	H	7c	90
4	CH3	H	H	OCH3	7d	93
5	OCH3	H	H	H	7e	95
6	OCH3	H	H	OCH3	7f	92
7	H	H	H	OCH3	7g	94
8	CN	H	H	OCH3	7h	90
9	CN	H	H	H	7i	91
10	H	H	H	Cl	7j	89
			H	H	7k	95
			H	OCH3	7l	93
			H	CN	7m	91
14	OH	Br	Br	H	7n	90
15	OH	Cl	Cl	H	7o	89
16	OH	Br	Br	OCH3	7p	96
17	OH	Cl	Cl	OCH3	7q	90

^aIsolated yield;

^bAll the compounds were characterized by ¹H NMR, ¹³C NMR, DEPT-135, IR and HRMS analysis.

Compounds 7a-q were obtained in 89-96% yields with high melting point (>300 °C). They were insoluble in usual organic solvent, water or hexane. The IR (KBr) spectra of compounds 7a-q exhibit absorption bands due to the stretching vibrations of NH group of indole cycles (3200 cm⁻¹ range). The spectra of compounds 7a-q display characteristic bands and C=S group (intense bands at 1628-1610 cm⁻¹). The 3-phenyl due to stretching vibrations of two C=O groups (1720 cm⁻¹ range -2-thioxothiazolidin-4-ones (3a-h) derivatives were prepared by the literature⁹ procedure by refluxing equimolar amounts of suitably substituted aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes 6a-d were synthesized by treating corresponding acid chlorides with HSnBu₃.¹⁰ The acid chlorides were prepared by acylation of indole (or substituted indole) with oxalylchloride.¹¹ All compounds were characterized by ¹H NMR, ¹³C NMR, DEPT-135, IR and HRMS studies.

In conclusion we have successfully developed an easy access to a novel series of (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives. The mild reaction conditions, easy workup, good to excellent yields, and easily available substrate make this reaction an attractive method for the preparation of 3-phenyl-2-thioxothiazolidin-4-ones. Efforts towards the synthesis of other important drug molecules with a Rhodanine moiety by MW irradiation are ongoing in our laboratory. Also work is in progress to obtain biological activity (antibacterial, antifungal, anticancer and neuroprotective kinase inhibitor activity) of these important compounds. Results in these areas will be presented in due course.

Table 2.

Reaction of various aromatic amines with di-(carboxymethyl)-trithiocarbonyl

Entry	R1	R2	R3	Time (h)	Product	Yielda (%)
1	H	H	H	3.0	3a	75
2	CH3	H	H	2.5	3b	73
3	CH3	CH3	H	2.5	3c	76
4	OCH3	H	H	2.0	3d	75
5	CN	H	H	4.0	3e	71
6	OH	Br	Br	3.0	3f	78
7	OH	Cl	Cl	3.0	3g	76
			H	4.0	3h	75

^aIsolated yield.