Synthesis under microwaves irradiation, structure elucidation, docking study for inhibiting COVID-19 and DFT calculations of novel azoles incorporated indole moiety

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Highlights

Abstract

In short reaction time with excellent yield, we designed and synthesized a series of indole linked azole ring at position-2 as thiazole and pyrazole moieties under microwaves irradiation. The structures and mechanistic pathways were discussed in this context using all available spectroscopic techniques. On the other hand, in some cases, the spectral data failed to differentiate and confirm the actual structure of some reactions, thus, we used the functional density theory calculations performed at the B3LYP/6-31G (d, p) level of the theory in order to distinguish the most stable derivative. The antimicrobial activity of selected derivatives showed moderate to good activity against some strains of bacteria and fungi while, indole-linked-pyrazole derivative 20 showed superior antifungal activity against Aspergillus fumigatus. Moreover, the pharmacokinetic and pharmacodynamic profiles were calculated and studied for all synthesized indole derivatives. Using the Molecular docking to study the affinities of the new derivatives to binding site of three SARS-CoV-2 enzymes (polymerase, helicase, and methyltransferase) to investigate their antiviral activity against SARS-CoV-2. The results indicated that all compounds have excellent energy level; docking scores from -6.5 to – 8.7 Kcal/mol in comparison with ligand score -5.5 Kcal/mol.

Introduction

Indole moiety is prevalent in many biologically active natural products. It is considered to be one of the most distinctive pillars of drug discovery [1]. There is a growing interest in using indole derivatives as biologically active molecules toward microbes and several types of cancer cells, as well as various types of disorders in the human body [2,3]. A lot of simple indole derivatives was reported as antimicrobial and antifungal agents in several studies as compounds I [4] and II [5] (Fig. 1). Also, the use of indole scaffold is widespread in antiviral research such as Delavirdine III [6] and Arbidol IV [7]. While a number of indole-derivatives go through clinical stages, such as Fosdevirine V and Atevirdine VI [6] (Fig. 1). On the other side, the presence of azole rings as pyrazoles, thiazoles or triazoles as a part of the heterocyclic systems enhances its biological efficiency as an antidote to many diseases [8], [9], [10], [11]. Thus, drugs have pyrazole in their skeleton showed potent activity against microbial [12], cancer [13] and diabetes [14]. Moreover, thiazole moiety is a vital part of several known drugs [15], and has shown a wide spectrum of therapeutic such as analgesic [16], anti-inflammatory [17,18], anticancer [19] and antimicrobial [20] activities. Thus, we interested to combine the indole ring with thiazole or pyrazole moiety to synthesize new bioactive compounds in short reaction time. For achieving the synthesis of new bioactive drugs in short reaction time. In order to be able to obtain effective bioactive drugs in a short period of time, we have found from literature reports that the best way is to heat the reaction mixture under microwaves irradiation [21], [22], [23]. Considering the (1H-indol-2-yl) residue, thiazole and pyrazole moieties as the pharmacophoric groups for the activity, we focused on the synthesis of a series of new derivatives carrying indole with thiazole or pyrazole moiety, with the aim of testing their antimicrobial activity. Due to the current COVID-19 disease has caused millions of deaths and dangerous pleural effects for many patients, we find that the whole world is in continuous search for effective drugs for this disease. Therefore, we tried in this research article to theoretically examine the new prepared derivatives using the Molecular docking for their affinities to binding site of three SARS-CoV-2 enzymes (polymerase, helicase, and methyltransferase) to investigate their antiviral activity against SARS-CoV-2.

Structure modification of compounds I and IV and design of target compounds represented in Fig. 2.

Section snippets

Results and discussion

Our aim to synthesize bioactive azoles incorporated indole moiety was achieved through the synthesis of starting 1H-indole-2-carboxylic acid (mercapto-phenylamino-methylene)-hydrazide 3 as depicted in Scheme 1. Reaction of 1H-indole-2-carboxylic acid ethyl ester 1 with hydrazine hydrate at room temperature afforded the acid hydrazide derivative 2 [24], [25], [26] followed with reaction with phenylisothiocyanate under microwaves irradiation to give our target starting compound 3 in ten min. (

Pharmacokinetics calculations

Any compound to be considered as a potential drug candidate should have acceptable pharmacokinetic and pharmacodynamic profiles, as well as a high safety margin. Thus, a computational study of the active antimicrobial compounds 3, 11a, b, d, 15a, 20 and 23B was performed to evaluate physicochemical properties and ADME using http://www.swissadme.ch/index.php of SwissADME server, Molsoft server (https://www.molsoft.com) and Pre‐ADME server (https://preadmet.bmdrc.kr) websites, and DataWarrior

Docking studies

Coronavirus disease-2019 (COVID-19) is the worst respiratory disease epidemic in a decade, caused by SARS-CoV-2, a novel enveloped positive-sense single-stranded RNA betacoronavirus. The Protein Data Bank provided the crystal structures of RNA dependent RNA polymerase (RdRp), Nsp13 helicase, and 2′-Omethyltransferase transferase (PDB IDs: 7bv2, 5rma and 6wkq, respectively). Autodock Vina was used to perform the docking trials, which requires both the receptor and the ligands to be in pdbqt

Conclusion

Finally, we are happy with what we found through the docking study concerning the theoretical ability of the indole-linked-thiazole or indole-linked-pyrazolone derivatives could aid in COVID-19 drug discovery as they maintained close affinity with the binding site of the Polymerase, Helicase and /or 2′ O-RNA methyltransferase of COVID-19. The new indole-linked-azole derivatives were prepared in minutes with excellent yield under microwaves irradiation. The structures and mechanistic pathways

Experimental

Melting points of indole derivatives 3-5, 11, 15, 20, 21 and 23 have been recorded on a Gallenkamp device without any correction. IR spectra of the same indole derivatives 3-5, 11, 15, 20, 21 and 23 have been detected as disc after grinding with KBr on spectrophotometer (Pye-Unicam SP300). All spectra of NMR (1H & 13C) for indole derivatives have been recorded in DMSO-d6 as solvent on a Varian Gemini 300 NMR spectrometer. In addition, The molecular weight of all indole derivatives have been

Synthesis of thiosemicarbazide derivative (3) under microwaves irradiation

Put in a HP-500 reaction vessel of the microwave device 2 mmole of hydrazide compound 2 with 2.2 mmole of PhNCS in 20 mL pure ethanol then irradiate the vessel in the microwave device under pressurized conditions at 800 W power at temperature 100 °C for 10 min. The solid product was formed on cooling, filtrated and washed with methanol. The crude product was recrystallized using ethanol to afford compound 3 as white solid, m.p 195-197 °C, IR ύ: 3296, 3212, 3116 (4NH), 3049 (sp2-CH), 1661 (C=O),

Synthesis of [5-(1H-indol-2-yl)-[1,3,4]oxadiazol-2-yl]-phenyl-amine (4) under microwaves irradiation

Under microwave irradiation (800 W, 110 °C), cyclization of compound 3 (2 mmole) in 15 mL pyridine was refluxed in microwave vessel for 12 min (checked by TLC after each 4 min). After the solution was cold at ordinary temperature, it was poured into ice water. The formed yellow solid was collected and crystallized from ethanol to afford compound 4 as yellow solid, yield 87%; mp 257-258 °C. IR ύ: 3380, 3249 (2NH), 2917 (sp3-CH), 1590 (Cdouble bondN), 1533, 1485, 1436, 1309, 1229, 1188, 1051 cm−1; 1H NMR

Synthesis of 5-(1H-indol-2-yl)-4-phenyl-2,4-dihydro-[1,2,4]triazole-3-thione (5) under microwaves irradiation

Compound 3 (2 mmole) was cyclized under microwave irradiation (800W, 110 °C) in KOH (25 mL of 5% solution) in microwave vessel for 15 min (checked by TLC after each 5 min). After the solution was cold at ordinary temperature, it was poured into ice water and acidified with HCl(PH = 6-7). The formed solid was collected with filtration and crystallized from ethanol/dioxan mixture (3:1) to afford white solid with 95% yield, m.p. 282-284 °C [20]. MS m/z (%): 293 (M++1, 33), 292 (M+, 56), 284 (29),

Reaction of thiosemicarbazide derivative 3 with phenacyl bromide derivatives 6a-d and hydrazonoyl chlorides 12a-e under microwaves irradiation

Under microwaves irradiation equimolar quantities of 2.5 mmol of thiosemicarbazide derivative 3 and 2.5 mmol of phenacyl bromide derivatives 6a-d or 2.5 mmol of appropriate hydrazonoyl chlorides 12a-e in 20 mL ethanol containing TEA (2.5 mmol) were mixed and irradiated (800W power) under reflux for 15-25 min (the reaction progress was mentored by TLC) at 110 °C. After cooling the reaction mixture, the colored solid products were formed and collected with filtration, drying and crystallized from

1H-Indole-2-carboxylic acid [4-(4-bromo-phenyl)-2-phenylimino-thiazol-3-yl]-amide (11a)

Yellow solid, 90% yield, m.p 252-254 °C, IR ύ: 3380, 3239 (2NH), 3057 (sp2-CH), 2969 (sp3-CH), 1636 (Cdouble bondO), 1605, 1580 (Cdouble bondN), 1480, 1389, 1302, 1268, 1184, 1105 cm−1; 1H NMR (DMSO-d6) δ: 7.02-7.68 (m, 15H, Ar-H, Indole-H and Thiazole-H), 10.74 (s, 1H, NH), 12.15 (s, 1H, NH). Ms m/z (%) 491 (M++2, 4), 490 (M++1, 6), 489 (M+, 12), 449 (25), 419 (73), 418 (100), 391 (55), 152 (8), 91 (16), 78 (15). Anal. Calcd.For: C24H17BrN4OS (489.39) C, 58.90; H, 3.50; N, 11.45. Found: C, 58.74; H, 3.29; N, 11.31%.

1H-Indole-2-carboxylic acid [4-(4-chloro-phenyl)-2-phenylimino-thiazol-3-yl]-amide (11b)

Orange solid, 89% yield, m.p 246-248 °C, IR ύ: 3380, 3240 (2NH), 3060 (sp2-CH), 1630 (Cdouble bondO), 1587 (Cdouble bondN), 1486, 1338, 1304, 1269, 1184, 1095 cm−1; 1H NMR (DMSO-d6) δ: 7.01-7.70 (m, 15H, Ar-H, Indole-H and Thiazole-H), 10.70 (s, 1H, NH), 12.15 (s, 1H, NH). Ms m/z (%) 446 (M++2, 16), 445 (M++1, 47), 444 (M+, 97), 412 (56), 396 (60), 372 (94), 292 (67), 272 (88), 255 (64), 241 (63), 208 (99), 188 (100), 78 (46). Anal. Calcd.For: C24H17ClN4OS (444.94) C, 64.79; H, 3.85; N, 12.59. Found: C, 64.65; H,

1H-Indole-2-carboxylic acid (2-phenylimino-4-p-tolyl-thiazol-3-yl)-amide (11c)

Yellow solid, 88% yield, m.p 240-242 °C, IR ύ: 3381, 3299 (2NH), 3056 (sp2-CH), 2927 (sp3-CH), 1635 (Cdouble bondO), 1589 (Cdouble bondN), 1490, 1443, 1339, 1232, 1114, 1049 cm−1; 1H NMR (DMSO-d6) δ: 2.43 (s, 3H, CH3), 7.01-8.07 (m, 15H, Ar-H, Indole-H and Thiazole-H), 10.74 (s, 1H, NH), 12.14 (s, 1H, NH). Ms m/z (%) 424 (M+, 27), 419 (25), 358 (28), 346 (39), 303 (24), 275 (55), 237 (52), 203 (100), 165 (57), 138 (41), 121 (52), 92 (24). Anal. Calcd.For: C25H20N4OS (424.52) C, 70.73; H, 4.75; N, 13.20. Found: C,

1H-Indole-2-carboxylic acid [4-(4-methoxy-phenyl)-2-phenylimino-thiazol-3-yl]-amide (11d)

Brown solid, m.p 255-257 °C, IR ύ: 3379, 3229 (2NH), 3059 (sp2-CH), 2967 (sp3-CH), 1639 (Cdouble bondO), 1586 (Cdouble bondN), 1485, 1441, 1337, 1302, 1268, 1182, 1098 cm−1; 1H NMR (DMSO-d6) δ: 3.83 (s, 3H, OCH3), 6.80 (s, 1H, thiazole H), 7.01-7.68 (m, 14H, Ar-H and Indole-H), 10.74 (s, 1H, NH), 12.14 (s, 1H, NH). Ms m/z (%) 440 (M+, 27), 370 (87), 341 (75), 330 (44), 243 (39), 232 (68), 188 (75), 146 (100), 118 (40), 85 (40), 78 (42). Anal. Calcd.For: C25H20N4O2S (440.52) C, 68.16; H, 4.58; N, 12.72. Found: C,

1H-Indole-2-carboxylic acid (4-methyl-3-phenyl-5-p-tolylazo-3H-thiazol-2-ylidene)-hydrazide (15a)

Orange solid, 92% yield, m.p 180-182 °C, IR ύ: 3380, 3243 (2NH), 3019 (sp2-CH), 2972 (sp3-CH), 1643 (Cdouble bondO), 1596, 1530 (Cdouble bondN), 1453, 1351, 1305, 1222, 1111, 1023 cm−1; 1H NMR (DMSO-d6) δ: 2.30 (s, 3H, CH3), 2.45 (s, 3H, CH3), 7.01 (s, 1H, Indole-H), 7.02-7.11 (m, 4H, Ar-H, Indole-H), 7.22 (t, J = 8 Hz, 2H, Ar-H), 7.32-7.40 (m, 4H, Ar-H), 7.47 (d, J = 8 Hz, 1H, Indole-H), 7.65 (d, J = 8Hz, 2H, Ar-H), 10.79 (s, 1H, NH), 12.14 (s, 1H, NH). Ms m/z (%) 466 (M, 46), 438 (39), 390 (55), 363 (42), 336

1H-Indole-2-carboxylic acid [5-(4-chloro-phenylazo)-4-methyl-3-phenyl-3H-thiazol-2-ylidene]-hydrazide (15b)

Yellow solid, 91% yield, m.p 220-222 °C, IR ύ: 3427, 3150 (2NH), 3097 (sp2-CH), 2924 (sp3-CH), 1651 (Cdouble bondO), 1592 (Cdouble bondN), 1530, 1459, 1356, 1219, 1086 cm−1; 1H NMR (DMSO-d6) δ: 2.04 (s, 3H, CH3), 6.94-7.68 (m, 14H, Ar-H and Indole-H), 11.11 (s, 1H, NH), 12.12 (s, 1H, NH). Ms m/z (%) 488 (M++2, 14), 487 (M++1, 32), 485 (37), 445 (39), 435 (73), 385 (44), 380 (54), 352 (75), 297 (36), 284 (51), 269 (70), 262 (100), 208 (56), 113 (70), 105 (42), 78 (54). Anal. Calcd.For: C25H19ClN6OS (486.98) C, 61.66;

1H-Indole-2-carboxylic acid [4-methyl-5-(4-nitro-phenylazo)-3-phenyl-3H-thiazol-2-ylidene]-hydrazide (15c)

Orange solid, 89% yield, m.p 212-214 °C, IR ύ: br. 3387 (2NH), 2928 (sp3-CH), 1658 (Cdouble bondO), 1597 (Cdouble bondN), 1474, 1337, 1229, 1193, 1017 cm−1; 1H NMR (DMSO-d6) δ: 2.46 (s, 3H, CH3), 7.0-8.27 (m, 14H, Ar-H and Indole-H), 10.75 (s, 1H, NH), 11.75 (s, 1H, NH). Ms m/z (%) 497 (M+, 21), 495 (50), 422 (32), 388 (35), 356 (45), 211 (30), 197 (72), 165 (44), 152 (72), 146 (41), 134 (71), 121 (75), 104 (50), 77 (42). Anal. Calcd.For: C25H19N7O3S (497.53) C, 60.35; H, 3.85; N, 19.71. Found: C, 60.24; H, 3.65; N,

1H-Indole-2-carboxylic acid (4-methyl-3-phenyl-5-phenylazo-3H-thiazol-2-ylidene)-hydrazide (15d)

Yellow solid, 93% yield, m.p 185-187 °C, IR ύ: 3380, 3241 (2NH), 3021 (sp2-CH), 1639 (Cdouble bondO), 1595 (Cdouble bondN), 1534, 1468, 1341, 1225, 1018 cm−1; 1H NMR (DMSO-d6) δ: 2.46 (s, 3H, CH3), 7.01-7.68 (m, 15H, Ar-H and Indole-H), 10.79 (s, 1H, NH), 11.22 (s, 1H, NH). Ms m/z (%) 452 (M+, 18), 433 (72), 422 (96), 404 (96), 381 (61), 358 (44), 280 (34), 272 (100), 261 (73), 217 (89). Anal. Calcd.For: C25H20N6OS (452.53) C, 66.35; H, 4.45; N, 18.57. Found: C, 66.19; H, 4.30; N, 18.43 %.

1H-Indole-2-carboxylic acid [5-(2,4-dichloro-phenylazo)-4-methyl-3-phenyl-3H-thiazol-2-ylidene]-hydrazide (15e)

Yellow solid, 92% yield, m.p 205-207 °C, IR ύ: 3390, 3203 (2NH), 3059 (sp2-CH), 2923 (sp3-CH), 1664 (Cdouble bondO), 1586 (Cdouble bondN), 1507, 1432, 1352, 1229, 1178, 1096 cm−1; 1H NMR (DMSO-d6) δ: 2.30 (s, 3H, CH3), 7.0-7.68 (m, 13H, Ar-H and Indole-H), 10.74 (s, 1H, NH), 12.13 (s, 1H, NH). Ms m/z (%) 523 (M++2, 51), 521 (M++1, 19), 508 (75), 496 (49), 465 (50), 457 (51), 440 (47), 398 (54), 387 (59), 361 (87), 287 (34), 251 (44), 246 (100), 220 (99), 178 (42), 167 (82), 134 (61), 77 (80). Anal. Calcd.For: C25H18

Reaction of acid hydrazide 2 with 1,3-dicarbonyl compounds 17-19 under microwaves irradiation

A mixture of 2 mmol of each acid hydrazide 2 and 1,3-dicarbonyl compounds (acetylacetone 17, diethylmalonate 18 or ethylbenzoyl acetate 19) in 20 glacial acetic acid in microwave vessel was refluxed under microwaves irradiation for 15-20 min (checked by TLC). After the solution was cold at ordinary temperature, it was poured into ice water then the formed solid was collected with filtration and crystallized from ethanol/dioxan mixture (3:1).

(3,5-Dimethyl-pyrazol-1-yl)-(1H-indol-2-yl)-methanone

Antimicrobial activity screening

The antibacterial activity was measured using the method reported previously [21,23].

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Author Contributions Section

All authors participated in the experimental work, analysis the data, writing and revised the article

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