Indian Journal of ChemistryVol. 37B, March 1998, pp. 314 - 317

Synthesis, .antimalarial.and ~ti~acterial,..-.activity of l-chloro-2-formyl-

and pyrazolo[3 ,4-a ]carbazole derivatives

M Sekar & K ~.Rajcndra Prasad'"Department of Chemistry, Bharathiar University,

Coimbatore 641 046, India

Received 14 July 1997; accepted (revised) 22 Januaiy 1998

'" I-Oxo-I,2,3,4-tetrahydrocarbazoles Ia-f on reactionwith Vilsmeier Haack reagent (DMFIPOCI)) furnish therespective l-chloro-z-formylcarbazole derivatives18-fwhich on treatment with hydrazine hydrate in ethanolyield pyrazolo[3,4-a]carbazole derivatives a.-f. All thechloro formyl compounds ltr--fhave been tested for theirantimalarial activity against mosquito species and an-timicrobial activities in comparison with chloroam-phenicol as a reference compound." . '

Carbazoles have been found to be depresents ofcentral nervous system':' antihistamine, anticancer,antiinflammatory, psychotropic, antibiotic andmuscle relaxants':'. Also, some of their derivativeshave been reported to be associated with antimi-crobial activity'. These results prompted us tosynthesise various new carbazole derivatives likepyrano, pyrazino and carbazolyloxypropanolamines"?". In the present study we have concen-trated on the synthesis of new pyrazolocarbazolederivatives 3a-f from l-chloro-Z-formylcarbazolederivatives 2a-f and study oftheir antimalarial andantimicrobial potencies.

1-0xo-l,2,3,4-tetrahydrocarbazole la was re-

Note

acted with Vilsmeier Haack reagent (DMFIPOCI))at 80°C for 6 h to obtain yellow crystals of theproduct 2a, m.p. 156-58°C. Its IR spectrumshowed three prominent bands at 3350, 2850 and1660 cm' corresponding to N-H, formyl" groupC-H and carbonyl stretchings. Its IH NMR spec-trum showed the multiplet at 0 7.40-8.80 due to thepresence of C-3, C-4, C-5, C-6, C-7 and C-8 aro-matic protons. The formyl proton appeared as asinglet substantially downfield at 0 10.00 and theNH proton appeared as a broad singlet at 0 12.20.Its mass spectrum showed the molecular ion peak(M":) at rnJz 229 and the compound analysed forthe molecular formula CnHsNOCl. The structureof the product was thus assigned as l-chloro-z-formylcarbazole 2a.

The compound 2a was reacted with hydrazinehydrate in ethanol to afford pale yellow crystals of3a, m.p. 125-26°C. Its IR spectrum showed C=Nstretching at 1590 and the N-H stretching at 3350em". Its \H NMR spectrum showed the multipletat 07:00-9.00 for C-3, C-4, C-5,C-6, C-7, C-8 andC-9 protons. The N\-H and NIO-Hprotons appearedas two singlets at 0 11.60 and 11.30 respectively.The mass spectrum showed the molecular ion peakat (M+) 207 and elemental analysis: C 75.38, H4.39 and N 20.29 were in agreement with the mo-lecular formula C\3H~3' Based on spectral datathe compound was assigned the structure pyra-zo10[3,4-a ]carbazole 3a.

Extension of this Vilsmeiers reaction techniqueto compounds lb-f afforded 2b-f. The compounds2b-f on treatment with hydrazine hydrate gave rise

ONRHO

1.-1

DMF/P0Cl3

S-6 hr

5 4 6 5

6y'v'1 ~ 3 NH2-NH27QHI ~ 4•. 7 ..-:::2 -----,~ •. 8 ..-:::"-..R 8 N 1 CHO EtOH • S hr R 9 N II 3

H a H tf\j-N2a-f 3a-f 1 2

1,2.-1 :. R· Hb R.~H3c R=7-CH3

d R -6-CH3• R. 6-CIf R - 6-Br

3 • R-Hb R -9-CH3cR· 8-CH3

d R:o:7-CH3• R '"' 7-C1f R =7-Br

_·b;l~.t C' ~

Scheme I

NOTES 315

Table J-Physica1 and spectroscopic data of the compounds 2.-f

Compel Yield m.p. Mol. formula! IR(K.Br) ·H NMR (solventlCDCI,)(%) (0C) (v•••••.in em") (li, ppm)

2a 77 156-58 C13H,NoCl 1660 7.40-8.80 (m, tH, C,-H, C.-H, Cs-H,2850 C,-H, C7-H and C.-H), 10.00(5, tH, C2-CHO),3350 12.2O(br5, tH, NH).

2b 78 162-63 C••H.oNOCI 1680 2.50(5, 3H, C.-CH]), 7.20-8.40 (m, 5H,2750 C,-H, C.-H, Cs-H, C,-H and ~-H), 10.203350 (s, tH, C2-CHO), 12.20 (br s, tH, NH)

2c 71 125-28 C••H.oNOCI 1670 2.80 (s, 3H, C7-CH,), 7.20-8.00 (m, 5H,2925 C,-H, C.-H, Cs-H, C,-H and C.-H),3375 8.40 (s, IH, C2-CHO), 8.90 (br 5, IH, NH)

2d 77 135-37 C••H.oNOCI 1680 2.60 (5, 3H, C,-CH), 7.20-8.50 (m, 5H,2950 C)-H, C.-H, Cs-H, C7-H and Ca-H).3400 8.90 (s, IH, C2-CHO), 9.72 (br s, IH, NH)

2e 78 145-47 CI,H7NOCl2 1680 7.50-9.20 (m, 5H, C)-H, C.-H, Cs-H, C7-H2925 and Ca-H), 10.20 (s, IH, C2-CHO), 12.403350 (br s, IH, NH)

2f 79 158-60 C13H7NOBrCl 1660 7.50-8.90 (m, 5H, C)-H, C.-H, c-,~-H,2900 and Ca-H), 10.20 (s, tH, C2-CHO),3300 12.40 (br s, IH, NH)

'Satisfactory elemental analyseswere obtained; C±O.24,H±O.II%, N±O.12

Table IJ-Physical and spectroscopic data of the compounds 3a-f

Compel Yield m.p. Mol. formula' IR(KBr) ·H NMR (solventlCDCI)(%) (0C) (v•••••in em") (S, ppm)

3a 79 125-26 C13H,N, 1590 7.00-9.00 (m, 7H, C,-H, C.-H, Cs-H, C,-H,3350 C7-H, Ca-H and C,-H), 11.30 (5, tH, NH),

11.60 (s, IH, I-NH)3b 78 198-99 C••HIIN) 1600 2;60 (s, 3H, 9-CH,), 7.20-8.00 (m, 6H, C)-H,

3450 C.-H, Cs-H, C,-H, ~-H and C.-H), 11.25(s, IH, NH), 11.60 (s, IH, I-NH)

3c 79 175-76 C••HIIN) 1590 2.40 (s, 3H, 8-CH,), 7.20-8.40 (m, 6H, C)-H,3350 C.-H, Cs-H, C6-H, ~-H and C,-H), 8.60

(5, IH, NH), 8.90 (5, IH, I-NH)3d . 78 165-67 C••HIIN, 1590 2.50 (5, 3H, 7-CH), 7.20-9.00 (m, 6H, C)-H,

il<:. 3375 C.-H, Cs-H, C6-H, C.-H and C,-H), 11.40

t(5, IH, NH), 11.80 (s, IH, I-NH)

'. 3e 77 115-16 C13H.N,Cl 1600 7.20-9.20 (m, 6H, C)-H, C.-H, Cs-H, C6-H,~- --- 3400 C.-H and C,-H), 11.70 (s, IH, NH), 12.10

(s, IH, I-NH)3f 75 161-62 C.,H.N,Br 1600 7.30-8.50 (m, 6H, C)-H, C.-H, Cs-H, C,-H,

3400 C.-H and C,-H), 11.40 (s, tH, NH), 11.90(s, tH, I-NH)

, Satisfactory elemental analysis were obtained; C±O.24,H±O.II %, N±O.12

to the corresponding pyrozolocarbazoles 3b-f re-spectively (Scheme O.

.malarial activity:he laboratory the Anopheles stephensi mos-

.OJ larvae were reared. Compounds 2.-f tested

were prepared as 5% concentrated solution inmethanol and diluted with 200 mL rearing water in250 mL plastic tubs. The control tubes were pre-pared as 5% methanol solution and diluted with200 mL rearing water. In each tube (100) earlyforth instar larvae were released. Five test series

316 INDIAN 1. CHEM., SEC. B, MARCH 1998

were conducted with the larvae held at 27±I°C,10L:14D, 75%, relative humidity and fed ad libi-tum with finely ground dog biscuits. Each test se-ries was repeated for five times. The dead larvaewere removed after 24h. All the live pupae weretransferred to water, which had been treated withsame concentration of the test materials. Larvalmortality, percentage of pupation and adult emer-gence were recorded. The corrected mortality per-centage from the observed mortality percentagewas calculated by using Abbott's formula",

Antibacterial activityThe antibacterial activity of the newly synthe-

sized compounds was tested against the followingorganisms: Gram-positive-Staphylococcus aurensATCC 25923, NCTC 6571, DSM 1104 and Gram-negative-Escherichia coli ATCC 25823, NCTC1048, DSM 10.

The synthesised compounds 2a-f were tested fortheir antibacterial activity using agar cup diffusiontechniques and chloroamphenicol as standard ref-erence+". The minimum inhibitory concentrations(MIC) were calculated (Jlg em") against Staphylo-coccus aurens and Escherichia coli. The MIC val-ues were determined and calculated as previouslyreported 13. Table III shows the MIC (ug cm") val-ues for the compounds 2a-f.

The result revealed that the prepared compoundsexhibited pronounced antibacterial activity againstthe bacterial tested (Table III).

Experimental SectionMelting points were determined on a mettler in-

strument and are uncorrected. PMR spectra wererecorded in CDCl3 on a Bruker WH 270 MHz

Table III--Antibacterial activity of the l-chloro-z-formyl-carbazoles 2a-'

Compd MIC (J.lg em?(correlation coefficient)

E. coli S. aureus

2a2b2c2d2e2f

Chloramphenicol

1.75 (0:930)1.85 (0.758)1.45 (0.656)1.59 (0.820)1.98 (0.950)1.96 (0.980)4.50 (0.985)

1.30 (0.870)1.86 (0.775)1.62 (0.883)1.69 (0.819)1.80 (0.730)1.70 (0.694)4.32 (0.988)

spectrometers using TMS as an internal standard.Microanalyses were performed on Carlo Erba 1106and Perkin Elmer model 240 CHN analysers. Massspectra were recorded on a Finnigan MAT 8230GC-MS mass spectrometer. IR spectra were re-corded on a Perkin Elmer 597 spectrometer.

Preparation of l-chloro-2-formylcarbazoles2: General procedure: To a ice cooled and stirredsolution of l-oxo-l,2,3,4-tetrahydrocarbazole de-rivatives (0.002 mole) in 4 mL of dimethyl fora-mide 10 mL of POCI) was added dropwise understirring during 15 min. The reaction mixture wasstirred at room temp. for 30 min and then main-tained on a boiling water bath for 5 to 6 h. Thedark red reaction mixture was poured under stir-ring onto crushed ice. The solid obtained was fil-tered, washed with water and chromatographedover silica with pet. ether-ethyl acetate as eluent(1:1). Their physical and spectroscopic data aregiven in Table I.

Preparation of pyrazolo[3,4-a]carbazole 3:General procedure: The chloroformyl compound(0.02 mole) was refluxed with 5 mL (excess) hy-drazine hydrate in ethanol for 5 h. The reactionmixture was then cooled and poured onto crushedice. The solid formed was filtered, washed withwater, and chromatographed over silica gel andeluted with ethyl acetate-pet. ether (5:1) as eluent.The physical and spectrascopic data are given inTable II.

AcknowledgementWe thank RSIC, CDRI, Lucknow and RSIC,

IISC Bangalore for PMR and mass spectral andelemental analyses. One of us (MS) thanks CSIR,New Delhi for the award of SRF. We are alsothankful to Dr M Murugan, Lecturer, Departmentof Zoology and Dr D Srinivasan, Department ofEnvironmental Science, Bharathiar University forproviding antimalarial and antibacterial activitydata.

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NOTES 317

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