Synthesis and Antimicrobial Activity of Some New Benzimidazole Derivatives

Afaf H. El-masry; H. H. Fahmy; S. H. Ali Abdelwahed

doi:10.3390/51201429

,

and

Therapeutical Chemistry Department. National Research Centre, Dokki, Cairo, Egypt

^*

Author to whom correspondence should be addressed.

Molecules2000, 5(12), 1429-1438;https://doi.org/10.3390/51201429

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Abstract

Reaction of 3-(2-methylbenzimidazol-1-yl)propanoic acid hydrazide (1) with CS₂/KOH gave oxadiazole 2 which underwent Mannich reaction to give 3. Compound 2 was treated with hydrazine hydrate to give triazole 4 which was treated with both aldehydes and acetic anhydride to give 5 and 6, respectively. Carbohydrazide 1 was reacted with ethyl acetoacetate, acetylacetone and aldehydes to give 7, 8 and 9, respectively. Cyclocondensation of 9 with thioglycolic and thiolactic acids gave 10 and 11, respectively. Some of these compounds showed potential antimicrobial activities.

Keywords:

Methylbenzimidazole; oxadiazole; thioglycolic; thiolactic; triazole; pyrazole; antimicrobial

Introduction

A wide variety of benzimidazole derivatives have been described for their chemotherapeutic importance [1,2,3,4,5,6]. Oxadiazole compounds have shown biological activity against parasites [7] and bacteria [8]. Also, the presence of basic Mannich side chains in a drug may overcome the water insolubility problem through the formation of hydrochlorides [9]. Also, some heterocyclic moieties such as triazole nucleus are known to possess antibacterial [10] and fungicidal [11] properties. Furthermore, Schiff’s bases possess anticancer [12,13] activity in animal screening, and pyrazoles, pyrazolones and alkylpyrazoles have shown wide ranging pharmacological applications [14]. We report here the synthesis of some derivatives of the title structure type containing the above mentioned moieties for evaluation of their antimicrobial activity.

Results and Discussion

In the present work, 3-(2-methylbenzimidazol-1-yl)propanoic acid hydrazide (1), which was previously prepared by one of us [15], was used as the key intermediate for further synthesis. Thus, when compound 1 was treated with carbon disulphide and potassium hydroxide according to a reported method of Young and Wood [8,16], 5-[2-(2-methylbenzimidazol-1-yl)ethyl]-[1,3,4]-oxadiazole-2(3H)-thione (2) was obtained, (Scheme 1, Table 2 and Table 3). One of the earliest discoveries concerning the utility of Mannich bases as intermediates in drug synthesis was made by Burckhalter and co-workers [17]. Similarly, compound 2 was allowed to undergo the Mannich reaction with different secondary amines namely, diethylamine, morpholine or N-methylpiprazine and paraformaldehyde in absolute ethanol to give compounds 3a-c respectively. (Scheme 1, Table 2 and Table 3).

A benzimidazole incorporated into a triazole moiety was synthesized by the reaction of 2 with hydrazine hydrate (99%) in absolute ethanol which afforded 1-[(1-amino-2-mercapto-1,3,4-triazol-5-yl)ethyl]-2-methylbenzimidazole (4). (Scheme 1, Table 2 and Table 3).

A number of arylidine hydrazones incorporated into the parent benzimidazole were also synthesized. Thus condensation of compound 4 with aromatic aldehydes, namely, p-methoxy benzaldehyde and o-chlorobenzaldehyde in absolute ethanol afforded the corresponding Schiff’s bases 5a,b respectively. (Scheme 1, Table 2 and Table 3).

Scheme 1.

On the other hand, reaction of 4 with acetic anhydride in the presence of glacial acetic acid leads to the formation of monoacetyl derivative 6. (Scheme 1, Table 2 and Table 3).

Carbohydrazide 1 was also allowed to react with ethyl acetoacetate and acetylacetone to give the corresponding methylpyrazolone derivative 7 and dimethylpyrazole derivative 8 respectively. (Scheme 2, Table 1 and Table 3). Condensation of compound 1 with aromatic and heterocyclic aldehydes in absolute ethanol afforded the corresponding Schiff’s bases 9a-f. (Scheme 2, Table 2 and Table 3).

Also, the cyclocondensation of some substituted Schiff’s bases with thioglycolic acid and thiolactic acid afforded the corresponding thiazolidinone 10a-c and methylthiazolidines 11a-c respectively. (Scheme 2, Table 2 and Table 3). This result is in accordance with previous reported results [18,19].

Scheme 2.

Biological Screening. Antimicrobial activity test

The test was performed according to the disk diffusion method [20] adopted with some modifications for the prepared compounds using Gentamycine and Ampicelline as references. The prepared compounds were tested against one strain of Gram +ve bacteria (Bacillus cereus), Gram –vebacteria (Escherichia coli), Yeast (Saccharomyces cerevisae) and Fungi (Aspergillus niger). Whatman No. 1 filter paper disk of 5mm diameter were sterilized by autoclaving for 15 min at 121°C . The sterile disks were impregnated with different compounds (600 μg / disk). Agar plates were surface inoculated uniformly from the broth culture of the tested microorganisms. The impregnated disks were placed on the medium suitably spaced apart and the plates were incubated at 5 °C for 1 h. to permit good diffusion and then transferred to an incubator at 37 °C for 24 h. for bacteria, and at 28 °C for 72 h. for yeast and fungi. The inhibition zones caused by the various compounds on the microorganisms were examined. The results of the preliminary screening test are listed in Table 1. The antibacterial and antifungal activity of compounds 1, 2, 3a, 4, 5b, 8, 9a, 10a,c and 11a,c were tested. From the data obtained in Table 1, it is clear that compound 2 was found to be highly active against Bacillus cereus but, slightly active against Escherichia coli. Compounds 4 and 9a were found to be moderately active against Bacillus cereus while compounds 3a and 10c were found to be slightly active against Bacillus cereus. But all the tested compounds were found to be inactive against Saccharomyces cerevisae and Aspergillus niger. Also, compounds 1, 5b, 8, 10a and 11a were found to be inactive against all microorganisms used.

Table 1. Results of antimicrobial activity of the tested compounds.

**Table 1.** Results of antimicrobial activity of the tested compounds.
Compound No.	B. cereus .	E. coli .	S. cerevisae .	A. niger .
Gentamycine	+++	+++	-	-
Ampicelline	+++	+++	-	-
1	-	-	-	-
2	+++	+	-	-
3a	+	-	-	-
4	++	-	-	-
5b	-	-	-	-
8	-	-	-	-
9a	++	-	-	-
10a	-	-	-	-
10c	+	-	-	-
11a	-	-	-	-
11c	-	+	-	-

Key to symbols:

Highly active = +++ (inhibition zone > 12 mm)
Moderately active = ++ (inhibition zone 9 - 12 mm)
Slightly active = + (inhibition zone 6 - 9 mm)
Inactive = - (inhibition zone < 6 mm)

Experimental

Materials and Methods

All melting points are uncorrected and were taken in open capillaries on a Gallenkamp apparatus. Infrared spectra were determined in KBr on a Perkin Elmer Model-137 Infracord. The ¹H-NMR spectra were measured in DMSO-d6 or CDCl₃ solutions using a JEOL EX-270MHz spectrometer. The mass spectra were recorded on a GCMS-QP 1000 EX Shimadzu Gas Chromatography-MS apparatus. Spectroscopic and physical data is listed in Table 2 and Table 3.

Synthesis of compounds

5-[2-(2-Methylbenzimidazol-1-yl) ethyl][1,3,4]oxadiazole-2(3H)-thione (2)

To a mixture of carbohydrazide 1 (2.18 g, 0.01 mole) in ethanol (200 mL) was added a solution of KOH (0.84 gm , 0.015 mole) in ethanol (20 mL), followed by CS₂ (20mL). The reaction mixture was heated under reflux for 8 hr. Then it was concentrated, acidified with dilute hydrochloric acid and the resulting solid was collected, washed with water and recrystallized to give compound 2.

5-[2-(2-Methylbenzimidazol-1-yl) ethyl]-3-diethylaminomethyl (or 3-N-morpholinylmethyl, or 3-N-piprazinylmethyl)[1,3,4]oxadiazole-2(3H)-thione (3a-c).

General method

A mixture of paraformaldehyde (0.9 g, 0.001mole) and the appropriate secondary amine, namely, diethylamine, morpholine or N-methylpiprazine (0.015 mole) was refluxed for 30 minutes in absolute ethanol (10 mL) until complete solubilization of the paraformaldehyde was observed. Compound 2 (1.04g, 0.004mole) was heated in absolute ethanol (10 mL), then added to the reaction mixture which was refluxed for 2 h. The reaction mixture was concentrated and the separated product was filtered off and recrystallized form chloroform/petroleum ether to give compounds 3a-c, respectively.

5-[2-(2-Methylbenzimidazol-1-yl) ethyl]-4-amino[1,2,4]triazole-3-thiol (4)

A mixture of compound 2 (2.6 g, 0.01 mole) and 99% hydrazine hydrate (2 mL, 0.03 mole) in absolute ethanol (20 mL) was refluxed for 6 h. The solvent and the excess hydrazine hydrate were removed under reduced pressure, the residue washed with ether, then recrystallized to give the product 4.

5-[2-(2-Methylbenzimidazol-1-yl)ethyl]-4-arylidenimino-[1,2,4]triazole-3-thiol (5a,b)

General method

To a solution of compound 4 (2.74 g, 0.01 mole) in absolute ethanol (30 mL), the appropriate aromatic aldehyde, namely, p−methoxybenzaldehyde or ο-chlorobenzaldehyde (0.012 mole) was added. The reaction mixture was refluxed for 4 h. The formed solid after cooling was filtered off and recrystallized to give the title compounds 5a,b, respectively.

5-[2-(2-Methylbenzimidazol-1-yl)ethyl]-4-actamido-[1,2,4]triazole-3-thiol (6)

Acetic anhydride (0.19 mL, 0.002 mole) was added to a boiling solution of 5-[2-(2-methyl-benzimidazol-1-yl) ethyl]-4amino[1,2,4]triazole-3-thiol (44) (0.28 g, 0.001 mole) in glacial acetic acid (3 mL). After refluxing for 2 h., the reaction mixture was cooled and poured into ice/cold water. The formed precipitate was filtered off and recrystallized from ethanol to give the title compound 6 .

1-[3-(2-Methylbenzimidazol-1-yl)propanoyl]-4,5-dihydro-3-methylpyrazol-5-one (7)

A mixture of carbohydrazide 1 (0.6 g, 0.0028 mole) and ethyl acetoacetate (0.364 g, 0.0028 mole) in absolute ethanol (20 mL) was heated at reflux temperature for 3 h. The reaction mixture was cooled and the formed precipitate was filtered off and recrystallized to give the title compound 7.

1-[3-(2-Methylbenzimidazol-1-yl)propanoyl]-3,5-dimethylpyrazole (8)

A mixture of compound I (0.6 g, 0.0028 mole) and acetylacetone (0.28 g, 0.0028 mole) in absolute ethanol (20 mL) was treated according to the procedure described above to give compound 8.

3-(2-Methylbenzimidazol-1-yl)propanoic acid hydrazide Schiff’s bases (9a-f )

General method

A mixture of compound 1 (2.2 g, 0.01 mole) and the appropriate aromatic or heterocyclic aldehyde, namely, o-chlorobenzaldehyde, p-nitrobenzaldehyde, p-methoxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, p-N,N-dimethylaminobenzaldehyde or 2-thiophenecarboxaldehyde (0.012 mole) was refluxed in absolute ethanol (20 mL) for 5 h. The reaction mixture was concentrated, cooled and the formed precipitate was filtered off, dried and then recrystallized to give the title compounds 9a-f respectively.

3-(2-Methylbenzimidazol-1-yl)-N-(2-aryl-4-oxo[1,3]thiazolidin-3-yl)propionamide (10a-c)

General method

A mixture of compound 9a,e,f (0.005 mole) and thioglycolic acid (0.55 g, 0.006 mole) was refluxed in dry benzene (50 mL) for 6 hr. The solvent was evaporated and the reaction mixture was neutralized with cold dilute sodium bicarbonate solution, the formed product was filtered off and recrystallized to give the title compounds 10a-c respectively.

3-(2-Methylbenzimidazol-1-yl)-N-(2-aryl-5-methyl-4-oxo[1,3]thiazolidin-3-yl)propionamide (11a-c)

General method

A mixture of compound 9a,b,f (0.005 mole) and thiolactic acid (0.65 g, 0.006 mole) was heated to fusion at 110-120 °C in an oil bath for 8 hr. The reaction mixture was neutralized with sodium bicarbonate solution, the formed product was filtered off and recrystallized to give the title compounds 11a-c respectively.

Table 2. Spectral data for the newly synthesized compounds.

**Table 2.** Spectral data for the newly synthesized compounds.
Compd. No	Spectral data
2	IR (KBr, cm^-1): 3300 (NH), 2923 (CH), 2600 (SH), 1624 (C=N) and 1136.0 (C=S), [(SH) and (C=S) absorptions indicate thiol-thione tautomers]. ¹H-NMR (DMSO-d₆, δ ppm): 2.55 (3H, s, CH₃ at C-2 of benzimidazole), 3.25 (2H, t, J = 7 Hz, NCH₂CH₂), 4.6 (2H, t, J = 7 Hz, NCH₂CH₂) and 7.25-7.6 (5H, m, aromatic protons, and SH). MS, m/z (%): 260 (M⁺, 57.72), 145 (100).
3a	IR (KBr, cm^-1): 2991 (CH), 1180 (C-O), 1654 (C=N) and 1150 (C=S). ¹H-NMR (CDCl₃, δ ppm): 1.2 (6H, t, J = 7 Hz, 2 CH₂CH₃), 2.55 (3H, s, CH₃ at C-2 of benzimidazole), 2.75 (2H, t, J = 7 Hz, NCH₂CH₂), 3.6 (4H, q, J = 6 Hz, 2 CH₂ CH₃), 4.45 (2H, t, J = 7 Hz, NCH₂CH₂), 4.9 (2H, s, NCH₂N) and 7.15-7.6 (4H, m, aromatic protons).
3b	IR: (KBr, cm^-1), 2985 (CH), 1177 (C-O), 1660 (C=N) and 1147 (C=S). ¹H-NMR (CDCl₃, δ ppm): 2.55 (4H, t, J = 7 Hz, N(CH₂)₂ of morpholine ring), 2.6 (3H, s, CH₃ at C-2 of benzimidazole), 3.2 (2H, t, NCH₂CH₂), 3.65 (4H, t, J = 7 Hz, O(CH₂)₂ of morpholine ring), 4.5 (2H, t, J = 7 Hz, NCH₂CH₂) 4.85 (2H, s, NCH₂N) and 7.15-7.7 (4H, m, aromatic protons).
3c	IR (KBr, cm^-1): 2988 (CH), 1176 (C-O), 1658 (C=N) and 1148 (C=S). MS: (M^+.,C₁₈H₂₄N₆OS), m/z 372.5 (0.09, unstable) and the base peak at m/z 145 (100).
4	IR (KBr, cm^-1): 3420, 3300, 3145 (NH₂ sym., asym-stretch and NH), 2600 (SH), 1155 (C=S) (thiol-thionetautomers) and 1620 (C=N). ¹H-NMR (DMSO-d₆, δ ppm): 2.5 (3H, s, CH₃ at C-2 of benzimidazole), 3.2 (2H, t, J = 7 Hz, NCH₂CH₂), 4.55 (2H, t, J = 7 Hz, NCH₂CH₂ ), 5.6 (2H, s, NH₂) and 7.25-7.6 (5H, m, aromatic protons and SH). MS, m/z (%):274 (M⁺ , 76.46), 145 (100).
5a	IR (KBr, cm^-1): 3047 (NH), 2993 (CH), 2580 (SH), 1267 (C=S) and 1153 (C-O). ¹H-NMR (DMSO-d₆, δ ppm): 2.5 (3H, s, CH₃ at C-2 of benzimidazole), 3.2 (2H, t, J = 7 Hz, NCH₂CH₂), 3.85 (3H, s, OCH₃), 4.55 (2H, t, J = 7 Hz, NCH₂CH₂) and 7.1-7.8 (8H, m, aromatic protons), 9.4 (1H, s, CH=N) and 13.8 (1H, s, NH). MS, m/z (%): 392 (M⁺ , 14.05), 132 (100).
5b	IR (KBr, cm-1): 3162 (NH), 2986 (CH), 2593 (SH), 1282 (C=S) and 746 (C-Cl). MS, m/z (%): 398 (M+, 37Cl, 0.29), 396 (M+, ³⁵Cl, 0.60), 132 (100).
6	IR (KBr, cm-1): 3157 (NH), 2964 (CH), 2486 (SH) and 1697 (C=O). MS, m/z (%): 316 (M+ , 16.1), 145 (100).
7	IR (KBr, cm^-1): 3210 (NH), 3005, 2995 (CH), 1732 (C=O, of pyrazolone), 1682 (C=O) and 1663 (C=N). ¹H-NMR (CDCl₃, δ ppm): 2.2 (3H, s, CH₃ at C-3 of pyrazolone), 2.5 (3H, s, CH₃ at C-2 of benzimidazole), 2.75 (2H, t, J = 7 Hz, NCH₂CH₂), 3.1 (2H, s, CH₂ of pyrazolone), 4.5 (2H, t, J = 7 Hz, NCH₂CH₂), and 7.15-7.6 (4H, m, aromatic protons). MS, m/z (%): 284 (M⁺ , 0.33), 145 (100).
8	IR (KBr, cm^-1): 2990 (CH) and 1668 (C=O). ¹H-NMR (CDCl₃, δ ppm): 1.55, 1.75 (6H, 2s, 2CH₃ of pyrazoline), 2.5 (3H, s, CH₃ at C-2 of benzimidazole), 2.95 (2H, t, J = 7 Hz,NCH₂CH₂), 4.45 (2H, t, J = 7 Hz, NCH₂CH₂) and 7.0-7.6 (5H, m, 4 aromatic protons and 1H of pyrazoline).
9a	IR (KBr, cm^-1): 3100 (NH), 2990 (CH), 1671 (C=O). MS, m/z (%): 342 (M⁺, ³⁷Cl, 20.7), 340 (M⁺, ³⁵Cl, 58.3), 145 (100).
9b	IR (KBr, cm^-1): 3045 (NH), 2964 (CH), 1671 (C=O), 1514, 1327 (NO₂).
9c	IR (KBr, cm^-1): 3190 (NH), 3000 (CH), 1670 (C=O). ¹H-NMR (CDCl₃, δ ppm): 2.45 (3H, s, CH₃ at C-2 of benzimidazole), 3.0 (2H, t, J = 7 Hz, NCH₂CH₂), 3.6 (3H, s, OCH₃), 4.35 (2H, t, J = 7 Hz, NCH₂CH₂), 6.65-7.7 (9H, m, 8 aromatic protons and 1H of N=CH) and 10.3 (1H, s, NH). MS, m/z (%): 336 (M⁺ , 100).
9d	IR (KBr, cm^-1): 3400 (OH), 3200 (NH), 2968(CH), 1664 (C=O). ¹H-NMR (DMSO-d₆ , δ ppm): 2.5 (3H, s, CH₃ at C-2 of benzimidazole), 3.0 (2H, t, J = 7 Hz, NCH₂CH₂), 3.7 (3H, s, OCH₃), 4.35 (2H, t, J = 7 Hz, NCH₂CH₂), 6.65-7.9 (8H, m, 7 aromatic protons and 1H of N=CH), 9.5 (1H, s, OH) and 11.1 (1H, s, NH). MS, m/z (%): 352 (M⁺ , 57), 145 (100).
9e	IR (KBr, cm^-1): 3251 (NH), 2984 (CH), 1672 (C=O). ¹H-NMR (DMSO-d₆ , δ ppm): 2.5 (3H, s, CH₃ at C-2 of benzimidazole), 2.95 (6H, s, N(CH₃)₂), 3.2 (2H, t, J = 7 Hz, NCH₂CH₂), 4.45 (2H, t, J = 7 Hz, NCH₂CH₂), 6.7-7.9 (9H, m, 8 aromatic protons and 1H of N=CH) and 11.1 (1H, s, NH).
9f	IR (KBr, cm^-1): 3209 (NH), 2997 (CH), 1668 (C=O).
10a	IR (KBr, cm^-1): 3417 (NH), 2930 (CH), 1716 (C=O of thiazolidinone), 1673 (C=O amide) and 746 (C-Cl). ¹H-NMR (DMSO-d₆, δ ppm): 2.5 (3H, s, CH₃ at C-2 of benzimidazole), 2.65 (2H, t, J = 7 Hz, NCH₂CH₂), 3.75 (1H, d, J = 6 Hz, A part of an AB system, equatorial proton of thiazolidinone at C-5), 3.9 (1H, d, J = 6 Hz, B part of an AB system, axial proton of thiazolidinone at C-5), 4.35 (2H, t, NCH₂CH₂), 6.00 (1H, s,CH of thiazolidinone at C-2 ), 7.1-7.5 (8H, m, aromatic protons) and 10.4 (1H, s, NH). MS, m/z (%): 416 (M⁺, ³⁷Cl, 3.62), 414 (M⁺, ³⁵Cl, 10.70), 132 (100).
10b	IR (KBr, cm^-1): 3415 (NH), 2951 (CH), 1719 (C=O of thiazolidinone), 1676 (C=O amide).
10c	IR (KBr, cm^-1): 3418 (NH), 2930 (CH), 1720 (C=O of thiazolidinone), 1677 (C=O amide). ¹H-NMR (DMSO-d₆, δ ppm): 2.45 (3H, s, CH₃ at C-2 of benzimidazole), 2.65 (2H, t, J = 7 Hz, NCH₂CH₂), 3.7 (1H, d, J = 6 Hz, A part of an AB system, equatorial proton of thiazolidinone at C-5), 4.0 (1H, d, J = 6 Hz, B part of an AB system, axial proton of thiazolidinone at C-5), 4.45 (2H, t, NCH₂CH₂), 5.95 (1H, s,CH of thiazolidinone at C-2 ), 6.7-7.5 (7H, m, aromatic protons) and 10.5 (1H, s, NH). MS, m/z (%): 386 (M⁺, 0.7), 132 (100).
11a	IR (KBr, cm^-1): 3400 (NH), 3000 (CH), 1715 (C=O of thiazolidinone), 1670 (C=O amide). ¹H-NMR (CDCl₃, δ ppm): 1.45 (3H, d, J = 6 Hz, CH₃ at C-5 of thiazolidinone), 2.45 (3H, s, CH₃ at C-2 of benzimidazole), 2.65 (2H, t, J = 7 Hz, NCH₂CH₂), 3.65 (1H, q, CH of thiazolidinone at C-5), 4.35 (2H, t, J = 7 Hz, NCH₂CH₂), 6.1 (1H, s, CH of thiazolidinone at C-2), 7.1-7.55 (8H, m, aromatic protons) and 10.4 (1H, s, NH). MS, m/z (%): 430 (M⁺, ³⁷Cl, 8.89), 428 (M⁺, ³⁵Cl, 25.78), 160 (100).
11b	IR (KBr, cm^-1): 3440 (NH), 2930 (CH), 1720 (C=O of thiazolidinone), 1677 (C=O amide) and 1520, 1325 (NO₂).
11c	IR (KBr, cm^-1): 3341 (NH), 3008 (CH), 1711 (C=O of thiazolidinone), 1675 (C=O amide). ¹H-NMR (DMSO-d₆, δ ppm): 1.43 (3H, d, J = 6 Hz, CH₃ at C-5 of thiazolidinone), 2.42 (3H, s, CH₃ at C-2 of benzimidazole), 2.65 (2H, t, J = 7 Hz, NCH₂CH₂), 3.65 (1H, q, CH of thiazolidinone at C-5), 4.4 (2H, t, J = 7 Hz, NCH₂CH₂), 6.2 (1H, s, CH of thiazolidinone at C-2), 6.9-7.5 (7H, m, aromatic protons) and 10.4 (1H, s, NH). MS, m/z (%): 400 (M⁺, 0.6), 132 (100).

Table 3. Yields, physical and analytical data of the prepared compounds.

**Table 3.** Yields, physical and analytical data of the prepared compounds.
Comp No.	M.P. °C (Recryst. Solvents)	Yield %	Formulae (M.Wt.)	Analysis % ,Calculated / Found
Comp No.	M.P. °C (Recryst. Solvents)	Yield %	Formulae (M.Wt.)	C	H	N	S
2	208-210 (AcOH/H2O)	86	C₁₂H₁₂N₄OS (260.28)	55.37 55.29	4.65 4.63	21.52 21.45	12.32 12.28
3a	89-91 (CHCl₃/Pet.ether)	65	C₁₇H₂₃N₅OS (345.51)	59.10 59.18	6.71 6.77	20.27 20.32	-
3b	183-185 (CHCl₃/Pet.ether)	60	C₁₇H₂₁N₅O₂S (359.49)	56.80 56.85	5.89 5.93	19.48 19.51	-
3c	149-150 (CHCl₃/Pet.ether)	63	C₁₈H₂₄N₆OS (372.54)	58.04 58.15	6.49 6.51	22.56 22.62	-
4	304-306 (AcOH/H₂O)	85	C₁₂H₁₄N₆S (274.35)	52.53 52.45	5.14 5.12	30.63 30.54	11.68 11.65
5a	261-263 (AcOH/H₂O)	80	C₂₀H₂₀N₆OS (392.48)	61.20 61.27	5.15 5.17	21.42 21.43	-
5b	249-251 (AcOH/H₂O)	85	C₁₉H₁₇ClN₆S (396.93)	57.49 57.53	4.32 4.37	21.18 21.21	-
6	282-284 (Ethanol)	68	C₁₄H₁₆N₆OS (316.43)	53.14 53.09	5.11 5.20	26.56 26.54	-
7	123-124 (Ethanol)	65	C₁₅ H₁₆ N₄ O₂ (284.35)	63.36 63.32	5.68 5.67	19.71 19.69	-
8	139-141 (Ethanol)	75	C₁₆ H₁₈ N₄ O (282.38)	68.06 68.09	6.43 6.47	19.85 19.90	-
9a	187-189 (Ethanol/H₂O)	87.5	C₁₈H₁₇ClN₄O (340.84)	63.43 63.41	5.04 5.01	16.44 16.40	-
9b	199-201 (Ethanol/H₂O)	82.6	C₁₈H₁₇N₅O₃ (351.36)	61.53 61.59	4.88 4.82	19.93 19.99	-
9c	167-169 (Ethanol/H₂O)	88	C₁₉H₂₀N₄O₂ (336.43)	67.84 67.87	6.00 6.12	16.66 16.69	-
9d	229-231 (Ethanol/H₂O)	90	C₁₉H₂₀N₄O₃ (352.43)	64.74 64.71	5.73 5.69	15.90 15.96	-
9e	179-181 (Ethanol/H₂O)	91	C₂₀H₂₃N₅O (349.48)	68.73 68.68	6.65 6.60	20.04 20.12	-
9f	89-91 (Ethanol/H₂O)	85	C₁₆H₁₆N₄OS (312.42)	61.51 61.56	5.17 5.20	17.93 17.99	-
10a	249-251 (Ethanol/H₂O)	71	C₂₀H₁₉ClN₄O₂S (414.94)	57.89 57.84	4.62 4.65	13.51 13.48	7.73 7.69
10b	264-266 (Ethanol/H₂O)	64	C₂₂H₂₅N₅O₂S (423.58)	62.39 62.45	5.96 5.98	16.54 16.58	7.55 7.60
10c	120-122 (Ethanol/H₂O)	40	C₁₈H₁₈N₄O₂S₂ (386.52)	55.94 55.98	4.70 4.69	14.49 14.46	16.59 16.55
11a	193-195 (CHCl₃/Pet.ether)	74	C₂₁H₂₁ClN₄O₂S (428.97)	58.80 58.87	4.94 4.96	13.06 13.11	7.47 7.50
11b	159-161 (Ethanol/H₂O)	53	C₂₁H₂₁N₅O₄S (439.53)	57.38 57.35	4.83 4.82	15.94 15.91	7.29 7.25
11c	131-133 (CHCl₃/Pet.ether)	44	C₁₉H₂₀N₄O₂S₂ (400.5)	56.97 57.12	5.04 5.11	13.99 14.13	16.00 16.10

Acknowledgements

The authors wish to express their thanks to Prof. Dr. Abdalhamid Ali Hamdy, Associate Professor, Department of Natural and Microbial Products Chemistry, National Research Centre, for his help with the biological testing .

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